experimental-infection-with-listeria-monocytogenes-as-model-for

Experimental Infection with <em>Listeria monocytogenes</em> as a Model for Studying Host Interferon-&#947; Responses

L. monocytogenes is a gram-positive bacterium that is a cause of food borne disease in humans. Experimental infection of mice with this pathogen has been ...

University of Toronto

Type 1 diabetes reflects autoimmune destruction of beta-cells and peri-islet Schwann cells (pSCs), but the mechanisms of pSC death and the T-cell epitopes involved remain unclear.

Targeting of pancreatic glia in type 1 diabetes.

While a number of microbial-associated molecular patterns have been known for decades to act as adjuvants, the mechanisms and the signaling pathways underlying their action have remained elusive. Here, we examined the unfolding of the adaptive immune response induced by Nod2 in vivo upon activation by its specific ligand, muramyl dipeptide, a component of peptidoglycan. Our findings demonstrate that this bacterial sensor triggers a potent Ag-specific immune response with a Th2-type polarization profile, characterized by the induction of IL-4 and IL-5 by T cells and IgG1 Ab responses. Nod2 was also found to be critical for the induction of both Th1- and Th2-type responses following costimulation with TLR agonists. Importantly, the synergistic responses to Nod2 and TLR agonists seen in vivo were recapitulated by dendritic cells in vitro, suggesting that these cells likely play a central role in the integration of Nod2- and TLR-dependent signals for driving the adaptive immune response. Taken together, our results identify Nod2 as a critical mediator of microbial-induced potentiation and polarization of Ag-dependent immunity. Moreover, these findings affect our understanding of Crohn's diseases pathogenesis, where lack of Nod2-dependent Th2 signaling in a subset of these patients might explain heightened Th1-mediated inflammation at the level of the intestinal mucosa.

Nod2-dependent Th2 polarization of antigen-specific immunity.

Recent advances in immunology have highlighted the critical function of pattern-recognition molecules (PRMs) in generating the innate immune response to effectively target pathogens. Nod1 and Nod2 are intracellular PRMs that detect peptidoglycan motifs from the cell walls of bacteria once they gain access to the cytosol. Salmonella enterica serovar Typhimurium is an enteric intracellular pathogen that causes a severe disease in the mouse model. This pathogen resides within vacuoles inside the cell, but the question of whether cytosolic PRMs such as Nod1 and Nod2 could have an impact on the course of S. Typhimurium infection in vivo has not been addressed. Here, we show that deficiency in the PRM Nod1, but not Nod2, resulted in increased susceptibility toward a mutant strain of S. Typhimurium that targets directly lamina propria dendritic cells (DCs) for its entry into the host. Using this bacterium and bone marrow chimeras, we uncovered a surprising role for Nod1 in myeloid cells controlling bacterial infection at the level of the intestinal lamina propria. Indeed, DCs deficient for Nod1 exhibited impaired clearance of the bacteria, both in vitro and in vivo, leading to increased organ colonization and decreased host survival after oral infection. Taken together, these findings demonstrate a key role for Nod1 in the host response to an enteric bacterial pathogen through the modulation of intestinal lamina propria DCs.

Role of Nod1 in mucosal dendritic cells during Salmonella pathogenicity island 1-independent Salmonella enterica serovar Typhimurium infection.

&#x6A21;&#x5F0F;&#x8BC6;&#x522B;&#x5206;&#x5B50; Nod1 &#x548C; Nod2 &#x626E;&#x6F14;&#x91CD;&#x8981;&#x7684;&#x89D2;&#x8272;&#xFF0C;&#x5728;&#x80A0;&#x9053;&#x5185;&#x7A33;&#x6001; &#xFF1B;&#x4E0D;&#x8FC7;&#xFF0C;&#x5982;&#x4F55;&#x5BF9;&#x7EC6;&#x83CC;&#x6027;&#x7ED3;&#x80A0;&#x708E;&#x708E;&#x75C7;&#x7684;&#x53D1;&#x5C55;&#x8FD9;&#x4E9B;&#x86CB;&#x767D;&#x8D28;&#x5F71;&#x54CD;&#x5C1A;&#x672A;&#x4E88;&#x4EE5;&#x5BA1;&#x67E5;&#x3002;&#x6C99;&#x95E8;&#x83CC;&#x7ED3;&#x80A0;&#x708E;&#x94FE;&#x9709;&#x7D20;&#x6CBB;&#x7597;&#x5C0F;&#x9F20;&#x6A21;&#x578B;&#xFF0C;&#x6211;&#x4EEC;&#x53D1;&#x73B0;&#x5C0F;&#x9F20;&#x4E0D;&#x8DB3; Nod1 &#x548C; Nod2 &#x4E86;&#x51CF;&#x6BD2;&#x708E;&#x6027;&#x75C5;&#x7406;&#x3001; &#x51CF;&#x5C11;&#x708E;&#x6027;&#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#x6C34;&#x5E73;&#x548C;&#x589E;&#x52A0;&#x7684;&#x9ECF;&#x819C;&#x7EC4;&#x7EC7;&#x7684;&#x6B96;&#x6C11;&#x5316;&#x3002;Nod1 &#x548C; Nod2 &#x9020;&#x8840;&#x548C; nonhematopoietic &#x6765;&#x6E90;&#x6709;&#x52A9;&#x4E8E;&#x75C5;&#x7406;&#x5B66;&#x548C;&#x6240;&#x6709;&#x8868;&#x578B;&#x4E0D;&#x8DB3;&#x4EE5;&#x5E94;&#x4ED8; Rip2 &#x4FE1;&#x53F7;&#x9002;&#x914D;&#x5668;&#x86CB;&#x767D;&#x7684;&#x5C0F;&#x9F20;&#x6982;&#x62EC;&#x3002;&#x7136;&#x800C;&#xFF0C;Rip2 &#x7684;&#x5F71;&#x54CD;&#x662F;&#x4E25;&#x683C;&#x4F9D;&#x8D56;&#x4E8E;&#x611F;&#x67D3;&#x6761;&#x4EF6;&#x9752;&#x7750;&#x7684;&#x8868;&#x8FBE;&#x7684;&#x6C99;&#x95E8;&#x83CC;&#x81F4;&#x75C5;&#x5C9B; 2 (SPI-2&#xFF09; &#x7C7B;&#x578B;&#x4E09;&#x3001; &#x5206;&#x6CCC;&#x7CFB;&#x7EDF; &#xFF08;TTSS&#xFF09;&#xFF0C;Rip2 &#x662F;&#x53EF;&#x6709;&#x53EF;&#x65E0;&#x7684;&#x708E;&#x75C7;&#x65F6;&#x5C0F;&#x9F20;&#x611F;&#x67D3;&#x4E86;&#x7EC6;&#x83CC;&#x5728;&#x4FC3;&#x8FDB;&#x8868;&#x8FBE;&#x7684; SPI 1 TTSS &#x7684;&#x6761;&#x4EF6;&#x4E0B;&#x751F;&#x957F;&#x3002;&#x56E0;&#x6B64;&#xFF0C;Nod1 &#x548C; Nod2 &#x53EF;&#x8C03;&#x8282;&#x708E;&#x75C7;&#x548C;&#x8C03;&#x89E3;&#x671F;&#x95F4;&#x6C99;&#x95E8;&#x6C0F;&#x83CC;&#x7ED3;&#x80A0;&#x708E;&#x7EC6;&#x83CC;&#x7684;&#x7C98;&#x819C;&#x7EC4;&#x7EC7;&#x9AD8;&#x6548;&#x8FC7;&#x5173;&#xFF0C;&#x4F46;&#x5B83;&#x4EEC;&#x7684;&#x4F5C;&#x7528;&#x662F;&#x53D6;&#x51B3;&#x4E8E;&#x8868;&#x8FBE;&#x7684; SPI 2 TTSS&#x3002;

&#x6C99;&#x95E8;&#x83CC;&#x7ED3;&#x80A0;&#x708E;&#x6A21;&#x578B;&#x4E2D;&#x708E;&#x75C7;&#x7684; Nod1 &#x548C; Nod2 &#x89C4;&#x7BA1;&#x3002;

The pattern recognition molecules Nod1 and Nod2 play important roles in intestinal homeostasis; however, how these proteins impact on the development of inflammation during bacterial colitis has not been examined. In the streptomycin-treated mouse model of Salmonella colitis, we found that mice deficient for both Nod1 and Nod2 had attenuated inflammatory pathology, reduced levels of inflammatory cytokines, and increased colonization of the mucosal tissue. Nod1 and Nod2 from both hematopoietic and nonhematopoietic sources contributed to the pathology, and all phenotypes were recapitulated in mice deficient for the signaling adaptor protein Rip2. However, the influence of Rip2 was strictly dependent on infection conditions that favored expression of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system (TTSS), as Rip2 was dispensable for inflammation when mice were infected with bacteria grown under conditions that promoted expression of the SPI-1 TTSS. Thus, Nod1 and Nod2 can modulate inflammation and mediate efficient clearance of bacteria from the mucosal tissue during Salmonella colitis, but their role is dependent on the expression of the SPI-2 TTSS.

Nod1 and Nod2 regulation of inflammation in the Salmonella colitis model.

Les mol&eacute;cules de reconnaissance de mod&egrave;le Nod1 et Nod2 jouent un r&ocirc;le important dans l&#39;hom&eacute;ostasie intestinale ; Cependant, comment ces impact de prot&eacute;ines sur le d&eacute;veloppement de l&#39;inflammation au cours de colite bact&eacute;rienne n&#39;a pas &eacute;tudi&eacute;. Dans le mod&egrave;le de souris trait&eacute;es &agrave; la streptomycine de colite de Salmonella, nous avons constat&eacute; que souris d&eacute;ficientes pour Nod1 et Nod2 avaient att&eacute;nu&eacute; la pathologie inflammatoire, des niveaux r&eacute;duits de cytokines inflammatoires et augment&eacute; la colonisation de la muqueuse. Nod1 et Nod2 provenant de sources nonhematopoietic et h&eacute;matopo&iuml;&eacute;tiques ont contribu&eacute; &agrave; la pathologie, et tous les ph&eacute;notypes ont &eacute;t&eacute; r&eacute;capitul&eacute;es dans les souris d&eacute;ficientes pour la signalisation de la prot&eacute;ine adaptatrice Rip2. Cependant, l&#39;influence de Rip2 &eacute;tait strictement d&eacute;pendante des conditions d&#39;infection que l&#39;expression privil&eacute;gi&eacute;e de la pathog&eacute;nicit&eacute; de Salmonella insulaire 2 (SPI-2) type III secretion system (TTSS), que Rip2 dispensable pour l&#39;inflammation quand les souris ont &eacute;t&eacute; infect&eacute;es par des bact&eacute;ries cultiv&eacute;es dans des conditions favorisant l&#39;expression de la TTSS SPI-1. Ainsi, Nod1 et Nod2 peuvent moduler l&#39;inflammation et m&eacute;diation efficace d&#39;apurement des bact&eacute;ries de la muqueuse au cours de colite de Salmonella, mais leur r&ocirc;le d&eacute;pend de l&#39;expression de la TTSS SPI-2.

Nod1 et Nod2 r&eacute;gulation de l&#39;inflammation dans le mod&egrave;le de colite de Salmonella.

Die Muster-Anerkennung-Molek&uuml;le Nod1 und Nod2 spielen wichtige Rollen in intestinalen Hom&ouml;ostase; jedoch ist wie diese Proteine-Auswirkungen auf die Entwicklung der Entz&uuml;ndung w&auml;hrend bakterielle Kolitis nicht &uuml;berpr&uuml;ft worden. Streptomyzin-behandelten Mausmodell der Salmonellen Kolitis fanden wir, dass M&auml;use mangelhaft f&uuml;r Nod1 und Nod2 entz&uuml;ndliche Pathologie abgeschw&auml;cht, Ebenen inflammatorische Zytokine reduziert und Kolonisierung von Schleimhaut-Gewebe erh&ouml;ht hatte. Nod1 und Nod2 aus h&auml;matopoetischen und nonhematopoietic Quellen dazu beigetragen, die Pathologie und alle Ph&auml;notypen wurden in den M&auml;usen unzul&auml;nglich f&uuml;r die Signalisierung Adapterprotein Rip2 rekapituliert. Jedoch war der Einfluss der Rip2 streng abh&auml;ngig von Infektion Bedingungen, dass die bevorzugte Ausdruck der Salmonellen-Pathogenit&auml;t 2 (SPI-2) Typ III-Sekretionssystem (TTSS), Insel, wie Rip2 entbehrlich f&uuml;r die Entz&uuml;ndung, war wenn M&auml;use infiziert waren, mit Bakterien, die unter Bedingungen, die Ausdruck der SPI-1 TTSS avanciert gewachsen. So Nod1 und Nod2 k&ouml;nnen modulieren Entz&uuml;ndung und effiziente Abfertigung der Bakterien aus dem Schleimhaut-Gewebe w&auml;hrend Salmonellen Kolitis zu vermitteln, aber ihre Rolle ist Ausdruck der SPI-2 TTSS abh&auml;ngig.

Nod1 und Nod2 Regulierung der Entz&uuml;ndung in der Salmonellen-Kolitis-Modell.

Le molecole di riconoscimento di pattern Nod1 e Nod2 giocano un ruolo importante nell&#39;omeostasi intestinale; Tuttavia, come questi impatto proteine sullo sviluppo di infiammazione durante la colite batterica non esaminata. Nel modello del mouse trattati con streptomicina di colite Salmonella, abbiamo trovato che topi carenti sia per Nod1 e Nod2 avevano attenuato la patologia infiammatoria, ridotti livelli di citochine infiammatorie e aumentata colonizzazione del tessuto della mucosa. Nod1 e Nod2 da fonti ematopoietiche e nonhematopoietic ha contribuito alla patologia, e tutti i fenotipi sono stati ricapitolati in topi carenti per la segnalazione della proteina adattatore Rip2. Tuttavia, l&#39;influenza del Rip2 era strettamente dipendente da condizioni di infezione che espressione favorita della patogenesi di Salmonella isola 2 (SPI-2) tipo sistema di secrezione di III (SS3), come Rip2 era superfluo per infiammazione quando topi sono stati infettati con batteri coltivati in condizioni che hanno promosso l&#39;espressione della SS3 SPI-1. Cos&igrave;, Nod1 e Nod2 pu&ograve; modulare l&#39;infiammazione e mediare efficiente liquidazione dei batteri dal tessuto della mucosa durante la colite Salmonella, ma dipende dal loro ruolo l&#39;espressione della SS3 SPI-2.

Regolamento Nod1 e Nod2 dell&#39;infiammazione nel modello di colite Salmonella.

&#x30D1;&#x30BF;&#x30FC;&#x30F3;&#x8A8D;&#x8B58;&#x5206;&#x5B50; Nod1 &#x3084; Nod2 &#x8178;&#x5185;&#x306E;&#x6052;&#x5E38;&#x6027;&#x306B;&#x91CD;&#x8981;&#x306A;&#x5F79;&#x5272;&#x3092;&#x679C;&#x305F;&#x3059;;&#x3069;&#x306E;&#x3088;&#x3046;&#x306B;&#x3057;&#x304B;&#x3057;&#x3001;&#x708E;&#x75C7;&#x306E;&#x958B;&#x767A;&#x4E2D;&#x306B;&#x7D30;&#x83CC;&#x306E;&#x8178;&#x708E;&#x3053;&#x308C;&#x3089;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x3078;&#x306E;&#x5F71;&#x97FF;&#x306F;&#x691C;&#x67FB;&#x3055;&#x308C;&#x306A;&#x304B;&#x3063;&#x305F;&#x3002;&#x30B5;&#x30EB;&#x30E2;&#x30CD;&#x30E9;&#x8178;&#x708E;&#x306E;&#x30B9;&#x30C8;&#x30EC;&#x30D7;&#x30C8;&#x30DE;&#x30A4;&#x30B7;&#x30F3;&#x51E6;&#x7406;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x306F;&#x3001;&#x6211;&#x3005; Nod1 &#x3084; Nod2 &#x306F;&#x6B20;&#x640D;&#x30DE;&#x30A6;&#x30B9;&#x3044;&#x305F;&#x708E;&#x75C7;&#x306E;&#x75C5;&#x7406;&#x3092;&#x6E1B;&#x8870;&#x3001;&#x708E;&#x75C7;&#x6027;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x306E;&#x30EC;&#x30D9;&#x30EB;&#x3092;&#x6E1B;&#x3089;&#x3057;&#x305F;&#x3057;&#x3001;&#x7C98;&#x819C;&#x7D44;&#x7E54;&#x306E;&#x690D;&#x6C11;&#x5730;&#x5316;&#x306E;&#x5897;&#x52A0;&#x304C;&#x898B;&#x3064;&#x304B;&#x308A;&#x307E;&#x3057;&#x305F;&#x3002;Nod1 &#x3084; Nod2 &#x9020;&#x8840;&#x3068; nonhematopoietic &#x306E;&#x4E21;&#x65B9;&#x306E;&#x30BD;&#x30FC;&#x30B9;&#x304B;&#x3089;&#x306F;&#x75C5;&#x7406;&#x5B66;&#x306B;&#x8CA2;&#x732E;&#x3057;&#x3001;&#x3059;&#x3079;&#x3066;&#x8868;&#x73FE;&#x578B;&#x3092;&#x30B7;&#x30B0;&#x30CA;&#x30EA;&#x30F3;&#x30B0;&#x306E;&#x30A2;&#x30C0;&#x30D7;&#x30BF;&#x30FC;&#x86CB;&#x767D;&#x8CEA; Rip2 &#x6B20;&#x640D;&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x518D;&#x8868;&#x73FE;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x708E;&#x75C7;&#x306E;&#x305F;&#x3081;&#x4E0D;&#x53EF;&#x6B20;&#x3067;&#x3057;&#x305F;&#x30DE;&#x30A6;&#x30B9; SPI 1 TTSS &#x306E;&#x767A;&#x73FE;&#x3092;&#x4FC3;&#x9032;&#x6761;&#x4EF6;&#x4E0B;&#x3067;&#x5897;&#x6B96;&#x3059;&#x308B;&#x7D30;&#x83CC;&#x306B;&#x611F;&#x67D3;&#x3057;&#x305F;&#x3068;&#x304D;&#x306B; Rip2 Rip2 &#x306E;&#x5F71;&#x97FF; 2 (SPI 2&#xFF09; &#x30BF;&#x30A4;&#x30D7; III &#x5206;&#x6CCC;&#x30B7;&#x30B9;&#x30C6;&#x30E0; (TTSS) &#x5CF6;&#x306E;&#x30B5;&#x30EB;&#x30E2;&#x30CD;&#x30E9;&#x75C5;&#x539F;&#x6027;&#x652F;&#x6301;&#x5F0F;&#x611F;&#x67D3;&#x6761;&#x4EF6;&#x306B;&#x53B3;&#x5BC6;&#x306B;&#x4F9D;&#x5B58;&#x3060;&#x3063;&#x305F;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;Nod1 &#x3084; Nod2 &#x3067;&#x304D;&#x307E;&#x3059;&#x708E;&#x75C7;&#x3092;&#x8ABF;&#x7BC0;&#x3057;&#x3066;&#x30B5;&#x30EB;&#x30E2;&#x30CD;&#x30E9;&#x8178;&#x708E;&#x306E;&#x4E2D;&#x306B;&#x7D30;&#x83CC;&#x306E;&#x7C98;&#x819C;&#x306E;&#x7D44;&#x7E54;&#x304B;&#x3089;&#x306E;&#x52B9;&#x7387;&#x7684;&#x306A;&#x901A;&#x95A2;&#x4EF2;&#x4ECB;&#x3057;&#x307E;&#x3059;&#x304C;&#x3001;&#x5F7C;&#x3089;&#x306E;&#x5F79;&#x5272;&#x306F; SPI 2 TTSS &#x306E;&#x5F0F;&#x306B;&#x4F9D;&#x5B58;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

&#x30B5;&#x30EB;&#x30E2;&#x30CD;&#x30E9;&#x8178;&#x708E;&#x30E2;&#x30C7;&#x30EB;&#x306B;&#x304A;&#x3051;&#x308B;&#x708E;&#x75C7;&#x306E; Nod1 &#x3084; Nod2 &#x898F;&#x5236;&#x3002;

&#xD328;&#xD134; &#xC778;&#xC2DD; &#xBD84;&#xC790; Nod1 &#xBC0F; Nod2 &#xC7A5;&#xB0B4; &#xD56D;&#xC0C1;&#xC131;;&#xC5D0; &#xC911;&#xC694; &#xD55C; &#xC5ED; &#xADF8;&#xB7EC;&#xB098;, &#xC5B4;&#xB5BB;&#xAC8C; &#xC138;&#xADE0;&#xC131; &#xB300; &#xC7A5; &#xC5FC; &#xB3D9;&#xC548; &#xC5FC;&#xC99D;&#xC758; &#xAC1C;&#xBC1C;&#xC5D0; &#xC774;&#xB7EC;&#xD55C; &#xB2E8;&#xBC31;&#xC9C8; &#xC601;&#xD5A5; &#xB418;&#xC9C0; &#xAC80;&#xC0AC; &#xD569;&#xB2C8;&#xB2E4;. &#xC0B4; &#xBAA8; &#xB12C; &#xB77C; colitis&#xC758; &#xC2A4; &#xCDE8;&#xAE09; &#xB9C8;&#xC6B0;&#xC2A4; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xC6B0;&#xB9AC;&#xB294; &#xC950; Nod1 &#xBC0F; Nod2 &#xACB0;&#xD54D; &#xD588;&#xB2E4; &#xC5FC;&#xC99D; &#xC131; &#xBCD1; &#xB9AC;&#xB97C; &#xAC10;&#xC1E0;, &#xC5FC;&#xC99D; &#xC131; cytokines&#xC758; &#xB808;&#xBCA8;&#xC744; &#xAC10;&#xC18C; &#xBC0F; &#xC810; &#xB9C9; &#xC870;&#xC9C1;&#xC758; &#xC2DD;&#xBBFC;&#xC9C0; &#xC99D;&#xAC00; &#xBC1C;&#xACAC;. Nod1 &#xBC0F; &#xC870; &#xD608; &#xBC0F; nonhematopoietic &#xC18C;&#xC2A4;&#xC5D0;&#xC11C; Nod2 &#xBCD1;&#xB9AC;&#xD559;&#xC5D0; &#xAE30;&#xC5EC; &#xD558; &#xACE0; &#xBAA8;&#xB4E0; &#xACE0;&#xAE30; &#xC2E0;&#xD638; &#xC5B4;&#xB311;&#xD130; &#xB2E8;&#xBC31;&#xC9C8; Rip2 &#xACB0;&#xD54D; &#xC0DD;&#xC950;&#xC5D0;&#xC11C; recapitulated &#xD588;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, &#xC950; &#xC2DD; SPI 1 TTSS&#xC758; &#xC2B9;&#xC9C4; &#xC870;&#xAC74; &#xD558;&#xC5D0;&#xC11C; &#xC131;&#xC7A5; &#xD558;&#xB294; &#xBC15;&#xD14C;&#xB9AC;&#xC544;&#xC5D0; &#xAC10;&#xC5FC; &#xD588;&#xB2E4; rip2&#xB294; &#xC5FC;&#xC99D;&#xC5D0; &#xB300; &#xD55C; &#xD544;&#xC218; Rip2 &#xC601;&#xD5A5; &#xAC10;&#xC5FC; &#xC870;&#xAC74; &#xC0B4; &#xBAA8; &#xB12C; &#xB77C; pathogenicity&#xC758; &#xC120;&#xD638; &#xC2DD; 2 (SPI-2) &#xC720;&#xD615; III &#xBD84; &#xBE44; &#xC2DC;&#xC2A4;&#xD15C; (TTSS) &#xC12C;&#xC5D0; &#xC5C4;&#xACA9; &#xD558; &#xAC8C; &#xB530;&#xB77C; &#xD588;&#xB2E4;. &#xB530;&#xB77C;&#xC11C; nod1&#xC640; Nod2 &#xC5FC;&#xC99D;&#xC744; &#xC870;&#xC808; &#xD558; &#xACE0; &#xC911;&#xC7AC; &#xC911; &#xC0B4; &#xBAA8; &#xB12C; &#xB77C; &#xB300; &#xC7A5; &#xC5FC;, &#xC810; &#xB9C9; &#xC870;&#xC9C1;&#xC5D0;&#xC11C; &#xBC15;&#xD14C;&#xB9AC;&#xC544;&#xC758; &#xD6A8;&#xC728;&#xC801; &#xD5C8;&#xAC00; &#xC218; &#xC788;&#xC9C0;&#xB9CC; &#xADF8;&#xB4E4;&#xC758; &#xC5ED;&#xD560;&#xC740; SPI 2 TTSS&#xC758; &#xC2DD;&#xC5D0; &#xB530;&#xB77C; &#xB2EC;&#xB77C; &#xC9D1;&#xB2C8;&#xB2E4;.

&#xC0B4; &#xBAA8; &#xB12C; &#xB77C; colitis &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xC5FC;&#xC99D;&#xC758; Nod1 &#xBC0F; Nod2 &#xADDC;&#xC81C;.

Las mol&eacute;culas de reconocimiento de patr&oacute;n Nod1 y Nod2 desempe&ntilde;an papeles importantes en la homeostasis intestinal; sin embargo, c&oacute;mo estas impacto de prote&iacute;nas en el desarrollo de la inflamaci&oacute;n durante la colitis bacteriana no se ha examinado. En el modelo de rat&oacute;n tratados con estreptomicina de Salmonella colitis, encontramos que ratones deficientes para Nod1 y Nod2 hab&iacute;an atenuado la patolog&iacute;a inflamatoria, reducci&oacute;n en los niveles de citoquinas inflamatorias y aument&oacute; la colonizaci&oacute;n de las mucosas. Nod1 y Nod2 de fuentes hematopoy&eacute;ticas y nonhematopoietic contribuyeron a la patolog&iacute;a, y todos los fenotipos se recapitulan en ratones deficientes para la prote&iacute;na adaptadora de se&ntilde;alizaci&oacute;n Rip2. Sin embargo, la influencia de Rip2 fue estrictamente depende de las condiciones de infecci&oacute;n que favorecido expresi&oacute;n de la patogenicidad de Salmonella isla (SPI-2) 2 tipo sistema de secreci&oacute;n III (TTSS), como Rip2 era prescindible para la inflamaci&oacute;n cuando ratones estaban infectados con bacterias cultivadas bajo condiciones que promueven la expresi&oacute;n de los TTSS de SPI-1. As&iacute;, Nod1 y Nod2 puede modular la inflamaci&oacute;n y mediar eficiente separaci&oacute;n de bacterias del tejido mucoso durante la colitis de Salmonella, pero su papel es dependiente en la expresi&oacute;n de los TTSS de SPI-2.

Nod1 y Nod2 la regulaci&oacute;n de la inflamaci&oacute;n en el modelo de colitis de Salmonella.

Sequence variants at or near the leucine-rich repeat kinase 2 (LRRK2) locus have been associated with susceptibility to three human conditions: Parkinson's disease (PD), Crohn's disease and leprosy. As all three disorders represent complex diseases with evidence of inflammation, we hypothesized a role for LRRK2 in immune cell functions. Here, we report that full-length Lrrk2 is a relatively common constituent of human peripheral blood mononuclear cells (PBMC) including affinity isolated, CD14(+) monocytes, CD19(+) B cells, and CD4(+) as well as CD8(+) T cells. Up to 26% of PBMC from healthy donors and up to 43% of CD14(+) monocytes were stained by anti-Lrrk2 antibodies using cell sorting. PBMC lysates contained full-length (>260 kDa) and higher molecular weight Lrrk2 species. The expression of LRRK2 in circulating leukocytes was confirmed by microscopy of human blood smears and in sections from normal midbrain and distal ileum. Lrrk2 reactivity was also detected in mesenteric lymph nodes and spleen (including in dendritic cells), but was absent in splenic mononuclear cells from lrrk2-null mice, as expected. In cultured bone marrow-derived macrophages from mice we made three observations: (i) a predominance of higher molecular weight lrrk2; (ii) the reduction of autophagy marker LC3-II in (R1441C)lrrk2-mutant cells (<31%); and (iii) a significant up-regulation of lrrk2 mRNA (>fourfold) and protein after exposure to several microbial structures including bacterial lipopolysaccharide and lentiviral particles. We conclude that Lrrk2 is a constituent of many cell types in the immune system. Following the recognition of microbial structures, stimulated macrophages respond with altered lrrk2 gene expression. In the same cells, lrrk2 appears to co-regulate autophagy. A pattern recognition receptor-type function for LRRK2 could explain its locus' association with Crohn's disease and leprosy risk. We speculate that the role of Lrrk2 in immune cells may also be relevant to the susceptibility of developing PD or its progression.

Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures.

&#x867D;&#x7136;&#x5927;&#x91CF;&#x7684;&#x7814;&#x7A76;&#x5BA1;&#x67E5;&#x4E86; T &#x8F85;&#x52A9;&#x7EC6;&#x80DE;&#x7C7B;&#x578B; 2 &#xFF08;Th2&#xFF09; &#x7684;&#x53D1;&#x5C55;&#x5728;&#x4E0D;&#x540C;&#x7684;&#x8BBE;&#x7F6E;&#xFF0C;&#x542F;&#x52A8;&#x6B64;&#x81C2;&#x7684;&#x81EA;&#x9002;&#x5E94;&#x514D;&#x75AB;&#x673A;&#x5236;&#x514D;&#x75AB;&#x4E0D;&#x597D;&#x7406;&#x89E3;&#x3002;&#x6211;&#x4EEC;&#x5229;&#x7528;&#x8FD9;&#x4E00;&#x4E8B;&#x5B9E;&#xFF0C;&#x514D;&#x75AB;&#x6297;&#x539F;&#x52A0;&#x4EFB;&#x4E00;&#x9F50;&#x805A;&#x6838;&#x82F7;&#x9178;&#x7ED3;&#x5408;&#x57DF;&#x5305;&#x542B;&#x86CB;&#x767D; 1 (Nod1) &#x6216; 2 (Nod2&#xFF09; &#x53D7;&#x4F53;&#x6FC0;&#x52A8;&#x5242;&#x9A71;&#x52A8;&#x5668; Th2 &#x611F;&#x5E94;&#x6765;&#x4E86;&#x89E3;&#x8FD9;&#x4E9B;&#x6A21;&#x5F0F;&#x8BC6;&#x522B;&#x53D7;&#x4F53;&#x5982;&#x4F55;&#x8C03;&#x89E3;&#x53D1;&#x5C55;&#x7684;&#x7CFB;&#x7EDF;&#x6027; Th2 &#x514D;&#x75AB;&#x53CD;&#x5E94;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x663E;&#x793A;&#x9AA8;&#x9AD3;&#x5D4C;&#x5408;&#x5C0F;&#x9F20;&#x57FA;&#x8D28;&#x8F66;&#x53A2;&#x5185;&#x7684; Nod1 &#x548C; Nod2 &#x8868;&#x8FBE;&#x5F0F;&#x662F;&#x5438;&#x6548;&#x5E94; CD4(+) Th2 &#x53CD;&#x5E94;&#x548C;&#x7279;&#x5B9A;&#x7684; IgG1 &#x6297;&#x4F53;&#x7684;&#x5FC5;&#x8981;&#x6761;&#x4EF6;&#x3002;&#x76F8;&#x6BD4;&#x4E4B;&#x4E0B;&#xFF0C;&#x8FD9;&#x4E9B;&#x914D;&#x4F53;&#x6811;&#x7A81;&#x72B6;&#x7EC6;&#x80DE;&#x4F20;&#x611F;&#x5E76;&#x4E0D;&#x8DB3;&#x4EE5;&#x8BF1;&#x5BFC; Th2 &#x514D;&#x75AB;&#x5E94;&#x7B54;&#xFF0C;&#x5C3D;&#x7BA1;&#x8FD9;&#x4E9B;&#x7EC6;&#x80DE;&#x5230;&#x54CD;&#x5E94;&#x7684;&#x8D21;&#x732E;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x6211;&#x4EEC;&#x786E;&#x5B9A; CD11c(+) &#x7EC6;&#x80DE;&#x662F;&#x91CD;&#x8981;&#x7684;&#x6297;&#x539F;&#x9012;&#x5448;&#x7EC6;&#x80DE;&#xFF0C;&#x800C; B &#x7EC6;&#x80DE;&#x548C;&#x55DC;&#x78B1;&#x4E0D;&#x5F71;&#x54CD;&#x70B9;&#x5934;&#x914D;&#x4F53;&#x7684;&#x80FD;&#x529B;&#xFF0C;&#x4FC3;&#x4F7F; CD4(+) Th2 &#x6548;&#x5E94;&#x529F;&#x80FD;&#x3002;&#x6700;&#x540E;&#xFF0C;&#x6211;&#x4EEC;&#x53D1;&#x73B0; Nod1 &#x548C; Nod2 &#x6FC0;&#x6D3B;&#x540E;&#x7684;&#x5145;&#x5206; Th2 &#x611F;&#x5E94;&#x53D6;&#x51B3;&#x4E8E;&#x4E24;&#x4E2A;&#x80F8;&#x817A;&#x57FA;&#x8D28; lymphopoietin &#x751F;&#x4EA7;&#x7684;&#x57FA;&#x8D28;&#x7EC6;&#x80DE;&#x4E0E; OX40 &#x914D;&#x4F53;&#x5BF9;&#x6811;&#x7A81;&#x72B6;&#x7EC6;&#x80DE;&#x5171;&#x523A;&#x6FC0;&#x5206;&#x5B50;&#x7684;&#x4E0A;&#x8C03;&#x3002;&#x8FD9;&#x9879;&#x7814;&#x7A76;&#x63D0;&#x4F9B;&#x4E86;&#x5982;&#x4F55;&#x7CFB;&#x7EDF;&#x6027; Th2 &#x514D;&#x75AB;&#x7684;&#x4F53;&#x5185;&#x8BC1;&#x636E;&#x8BF1;&#x5BFC;&#x70B9;&#x5934;&#x523A;&#x6FC0;&#x7684;&#x4E0A;&#x4E0B;&#x6587;&#x4E2D;&#x3002;&#x8FD9;&#x79CD;&#x7406;&#x89E3;&#x5C06;&#x4F1A;&#x5F71;&#x54CD;&#x53EF;&#x4EE5;&#x91CD;&#x65B0;&#x514D;&#x75AB;&#x7CFB;&#x7EDF;&#x7F16;&#x7A0B;&#x671F;&#x95F4;&#x79EF;&#x6781;&#x4ECB;&#x5BFC; Th1 &#x75BE;&#x75C5;&#x5982;&#x514B;&#x7F57;&#x6069;&#x75C5;&#x7684;&#x7597;&#x6CD5;&#x7684;&#x5408;&#x7406;&#x8BBE;&#x8BA1;&#x3002;

&#x6838;&#x82F7;&#x9178;&#x9F50;&#x805A;&#x57DF;&#x5305;&#x542B;&#x86CB;&#x767D;&#x8D28;&#x6307;&#x793A;&#x901A;&#x8FC7;&#x57FA;&#x8D28;&#x6FC0;&#x6D3B; T &#x7EC6;&#x80DE;&#x5E2E;&#x52A9;&#x5668; 2 &#x578B;&#x514D;&#x75AB;&#x3002;

Although a number of studies have examined the development of T-helper cell type 2 (Th2) immunity in different settings, the mechanisms underlying the initiation of this arm of adaptive immunity are not well understood. We exploited the fact that immunization with antigen plus either nucleotide-binding oligomerization domain-containing proteins 1 (Nod1) or 2 (Nod2) agonists drives Th2 induction to understand how these pattern-recognition receptors mediate the development of systemic Th2 immune responses. Here, we show in bone-marrow chimeric mice that Nod1 and Nod2 expression within the stromal compartment is necessary for priming of effector CD4(+) Th2 responses and specific IgG1 antibodies. In contrast, sensing of these ligands by dendritic cells was not sufficient to induce Th2 immunity, although these cells contribute to the response. Moreover, we determined that CD11c(+) cells were the critical antigen-presenting cells, whereas basophils and B cells did not affect the capacity of Nod ligands to induce CD4(+) Th2 effector function. Finally, we found that full Th2 induction upon Nod1 and Nod2 activation was dependent on both thymic stromal lymphopoietin production by the stromal cells and the up-regulation of the costimulatory molecule, OX40 ligand, on dendritic cells. This study provides in vivo evidence of how systemic Th2 immunity is induced in the context of Nod stimulation. Such understanding will influence the rational design of therapeutics that could reprogram the immune system during an active Th1-mediated disease, such as Crohn's disease.

Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation.

Bien qu&#39;un certain nombre d&#39;&eacute;tudes ont examin&eacute; le d&eacute;veloppement de cellules de T-helper type 2 (Th2) immunit&eacute; dans diff&eacute;rents contextes, les m&eacute;canismes sous-jacents &agrave; l&#39;ouverture de ce bras de l&#39;immunit&eacute; adaptative ne sont pas bien comprises. Nous avons exploit&eacute; le fait que l&#39;immunisation par l&#39;antig&egrave;ne ou l&#39;autre liaison nucl&eacute;otidique oligom&eacute;risation domaine contenant prot&eacute;ines 1 (Nod1) ou 2 (Nod2) agonistes lecteurs Th2 induction pour comprendre comment ces r&eacute;cepteurs de reconnaissance de motifs m&eacute;dient l&#39;&eacute;laboration de la r&eacute;ponse immunitaire syst&eacute;mique Th2. Nous montrons ici, chez les souris chim&eacute;riques de moelle osseuse qu&#39;expression Nod1 et Nod2 dans le compartiment du stroma est n&eacute;cessaire pour l&#39;amor&ccedil;age des r&eacute;ponses de CD4 + Th2 effectrices et anticorps IgG1 sp&eacute;cifiques. En revanche, de d&eacute;tection de ces ligands par des cellules dendritiques n&#39;&eacute;tait pas suffisante pour provoquer l&#39;immunit&eacute; Th2, bien que ces cellules contribuent &agrave; la r&eacute;ponse. En outre, nous avons d&eacute;termin&eacute; que les cellules CD11c(+) ont &eacute;t&eacute; les cellules pr&eacute;sentatrices d&#39;antig&egrave;ne critiques, alors que les basophiles et les cellules B n&#39;a pas affect&eacute; la capacit&eacute; des ligands de clin de &oelig;il pour induire la fonction effectrice CD4 + Th2. Enfin, nous avons constat&eacute; que la pleine induction Th2 3.1.?: Nod1 et Nod2 d&eacute;pendait de deux lymphopoietin du stroma thymique de production par les cellules stromales et la r&eacute;gulation de la mol&eacute;cule de costimulation, OX40 ligand, sur les cellules dendritiques. Cette &eacute;tude fournit des preuves in vivo de l&#39;immunit&eacute; syst&eacute;mique comment Th2 sont induite dans le contexte de la stimulation de Nod. Une telle compr&eacute;hension va influencer la conception rationnelle de produits th&eacute;rapeutiques qui pourraient reprogrammer le syst&egrave;me immunitaire au cours d&#39;une maladie &agrave; m&eacute;diation Th1 active, comme la maladie de Crohn.

Prot&eacute;ines nucl&eacute;otide oligom&eacute;risation domaine instruisent l&#39;immunit&eacute; lymphocytes T helper type 2, gr&acirc;ce &agrave; l&#39;activation du stroma.

Obwohl eine Reihe von Studien die Entwicklung der T-Helfer-Zelltyp 2 (Th2) untersucht haben Immunit&auml;t in unterschiedlichen Settings, die Mechanismen, die die Einleitung dieser Arm der adaptiven Immunit&auml;t sind nicht gut verstanden. Wir ausgenutzt der Tatsache, dass Immunisierung mit Antigen plus entweder Nukleotid-Bindung Oligomerisierung Dom&auml;ne-haltige Proteine 1 (Nod1) oder 2 (Nod2) Agonisten Laufwerke Th2 Induktion zu verstehen, wie diese Mustererkennung Rezeptoren die Entwicklung systemischer Th2-Immunantworten vermitteln. Hier zeigen wir im Knochenmark chimeric M&auml;use, dass Nod1 und Nod2 Ausdruck innerhalb der stromal Fach Grundierung der Effektor CD4(+) Th2 Antworten und spezifische IgG1-Antik&ouml;rper erforderlich ist. Dagegen war die Sensorik diese Liganden durch dendritische Zellen nicht ausreichend Th2 Immunit&auml;t, veranlassen, obwohl diese Zellen zu der Antwort beitragen. Dar&uuml;ber hinaus festgestellt wir, dass CD11c(+) Zellen die kritischen Antigen-pr&auml;sentierenden Zellen wurden, basophile und B-Zellen ber&uuml;hrt nicht die Kapazit&auml;t der Nod-Liganden CD4(+) Th2-Effektor-Funktion zu veranlassen. Schlie&szlig;lich fanden wir, dass vollst&auml;ndige Th2-Induktion bei Nod1 und Nod2 Aktivierung beider Thymom stromal Lymphopoietin-Produktion durch die stromal Zellen und bis-Regulierung der kostimulatorischen Molek&uuml;ls, OX40 Liganden dendritische Zellen abh&auml;ngig war. Diese Studie liefert, dass im Rahmen der Nod-Stimulation in-vivo Beweis wie systemische Th2 Immunit&auml;t induziert wird. Ein solches Verst&auml;ndnis beeinflussen das rationale Design von Therapeutika, die das Immunsystem w&auml;hrend einer aktiven Th1-vermittelten Krankheit, wie z. B. Morbus Crohn umprogrammieren k&ouml;nnte.

Nukleotid Oligomerisierung Dom&auml;ne-haltige Proteine weisen T Zell Helfer Typ 2 Immunit&auml;t durch stromal Aktivierung.

Sebbene un certo numero di studi hanno esaminato lo sviluppo della cellula di T-helper tipo 2 (Th2) immunit&agrave; in impostazioni differenti, i meccanismi sottostanti l&#39;avvio di questo braccio di immunit&agrave; adattativa non sono ben compresi. Abbiamo sfruttato il fatto che l&#39;immunizzazione con antigeni plus o nucleotide-binding oligomerization dominio contenenti proteine 1 (Nod1) o 2 (Nod2) agonisti unit&agrave; Th2 induzione per capire come questi recettori di riconoscimento mediano lo sviluppo di risposte di immunitario Th2 sistemiche. Qui, vi mostriamo in topi chimerici del midollo osseo che Nod1 e Nod2 espressione all&#39;interno del compartimento stroma &egrave; necessaria per l&#39;adescamento di effettori Th2 CD4(+) risposte e specifici anticorpi IgG1. In contrasto, rilevamento di questi leganti da cellule dendritiche non era sufficiente per indurre immunit&agrave; Th2, anche se queste cellule contribuiscono alla risposta. Inoltre, abbiamo determinato che le cellule CD11c(+) erano le cellule presentanti l&#39;antigene critiche, considerando che mastociti e basofili cellule B non influisce sulla capacit&agrave; di ligandi Nod per indurre la funzione effector CD4(+) Th2. Infine, abbiamo trovato piena Th2 induzione all&#39;attivazione Nod1 e Nod2 dipendeva da entrambi produzione lymphopoietin stromali del timo da cellule stromale e la up-regolazione della molecola costimolazione, OX40 ligando, sulle cellule dendritiche. Questo studio fornisce prove in vivo di immunit&agrave; Th2 come sistemico sono indotta nel contesto della stimolazione Nod. Tale comprensione influenzeranno il design razionale delle terapie che potrebbero riprogrammare il sistema immunitario durante una malattia attiva Th1-mediata, come la malattia di Crohn.

Dominio-contenente proteine oligomerizzazione di nucleotide istruire immunit&agrave; di tipo 2 delle cellule T helper tramite attivazione stromale.

&#x591A;&#x304F;&#x306E;&#x7814;&#x7A76; 2 (th1, Th2) &#x30D8;&#x30EB;&#x30D1;&#x30FC; T &#x7D30;&#x80DE;&#x578B;&#x306E;&#x958B;&#x767A;&#x3092;&#x691C;&#x8A0E;&#x3057;&#x3066;&#x3044;&#x308B;&#x304C;&#x7570;&#x306A;&#x308B;&#x8A2D;&#x5B9A;&#x3092;&#x958B;&#x59CB;&#x3053;&#x306E;&#x9069;&#x5FDC;&#x514D;&#x75AB;&#x306E;&#x8155;&#x306E;&#x4E0B;&#x306B;&#x3042;&#x308B;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x306B;&#x304A;&#x3051;&#x308B;&#x514D;&#x75AB;&#x3088;&#x304F;&#x7406;&#x89E3;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x305B;&#x3093;&#x3002;&#x6211;&#x3005; &#x306F;&#x514D;&#x75AB;&#x6297;&#x539F;&#x306B;&#x52A0;&#x3048;&#x3001;&#x3053;&#x308C;&#x3089;&#x30D1;&#x30BF;&#x30FC;&#x30F3;&#x8A8D;&#x8B58;&#x53D7;&#x5BB9;&#x4F53;&#x5168;&#x8EAB; Th2 &#x514D;&#x75AB;&#x53CD;&#x5FDC;&#x306E;&#x958B;&#x767A;&#x3092;&#x4EF2;&#x4ECB;&#x3059;&#x308B;&#x65B9;&#x6CD5;&#x3092;&#x7406;&#x89E3;&#x3059;&#x308B;&#x3044;&#x305A;&#x308C;&#x304B;&#x91CD;&#x5408;&#x306B;&#x304A;&#x3051;&#x308B;&#x30CC;&#x30AF;&#x30EC;&#x30AA;&#x30C1;&#x30C9;&#x7D50;&#x5408;&#x30C9;&#x30E1;&#x30A4;&#x30F3;&#x3092;&#x542B;&#x3080;&#x86CB;&#x767D;&#x8CEA; 1 &#xFF08;Nod1) &#x307E;&#x305F;&#x306F; 2 (Nod2&#xFF09; &#x30A2;&#x30B4;&#x30CB;&#x30B9;&#x30C8; &#x30C9;&#x30E9;&#x30A4;&#x30D6; Th2 &#x8A98;&#x5C0E;&#x3068;&#x3044;&#x3046;&#x4E8B;&#x5B9F;&#x3092;&#x60AA;&#x7528;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x9593;&#x8CEA;&#x30B3;&#x30F3;&#x30D1;&#x30FC;&#x30C8;&#x30E1;&#x30F3;&#x30C8;&#x5185; Nod1 &#x3084; Nod2 &#x5F0F;&#x304C;&#x30A8;&#x30D5;&#x30A7;&#x30AF;&#x30BF;&#x30FC; CD4(+) Th2 &#x5FDC;&#x7B54;&#x304A;&#x3088;&#x3073;&#x7279;&#x7570; IgG1 &#x6297;&#x4F53;&#x306E;&#x30D7;&#x30E9;&#x30A4;&#x30DF;&#x30F3;&#x30B0;&#x306E;&#x305F;&#x3081;&#x306B;&#x5FC5;&#x8981;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3067;&#x9AA8;&#x9AC4;&#x30AD;&#x30E1;&#x30E9;&#x30DE;&#x30A6;&#x30B9;&#x3092;&#x8868;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x7D30;&#x80DE;&#x5FDC;&#x7B54;&#x306B;&#x5BC4;&#x4E0E;&#x304C;&#x5BFE;&#x7167;&#x7684;&#x306B;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E; ligands &#x6A39;&#x72B6;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x308B;&#x30BB;&#x30F3;&#x30B7;&#x30F3;&#x30B0; Th2 &#x514D;&#x75AB;&#x3092;&#x8A98;&#x5C0E;&#x3059;&#x308B;&#x306E;&#x306B;&#x5341;&#x5206;&#x3060;&#x3063;&#x305F;&#x3002;&#x307E;&#x305F;&#x3001;CD11c(+) &#x306E;&#x30BB;&#x30EB;&#x306F;&#x91CD;&#x8981;&#x306A;&#x6297;&#x539F;&#x63D0;&#x793A;&#x7D30;&#x80DE;&#x3067;&#x3042;&#x3063;&#x305F;&#x3053;&#x3068;&#x306B;&#x597D;&#x5869;&#x57FA;&#x7403;&#x3068; B &#x7D30;&#x80DE; CD4(+) Th2 &#x30A8;&#x30D5;&#x30A7;&#x30AF;&#x30BF;&#x30FC;&#x6A5F;&#x80FD;&#x3092;&#x8A98;&#x3046;&#x80FD;&#x529B; Nod &#x914D;&#x4F4D;&#x5B50;&#x306E;&#x5F71;&#x97FF;&#x304C;&#x306A;&#x304B;&#x3063;&#x305F;&#x6C7A;&#x5B9A;&#x3002;&#x6700;&#x5F8C;&#x306B;&#x3001;&#x5B8C;&#x5168;&#x306A; Th2 &#x8A98;&#x5C0E; Nod1 &#x3084; Nod2 &#x6D3B;&#x6027;&#x5316;&#x4E21;&#x65B9;&#x9593;&#x8CEA;&#x7D30;&#x80DE;&#x3068;&#x5171;&#x523A;&#x6FC0;&#x5206;&#x5B50;&#x3001;&#x6A39;&#x72B6;&#x7D30;&#x80DE;&#x4E0A;&#x306E; OX40 &#x30EA;&#x30AC;&#x30F3;&#x30C9;&#x306E;&#x30A2;&#x30C3;&#x30D7;&#x898F;&#x5236;&#x306B;&#x3088;&#x308B;&#x80F8;&#x817A;&#x9593;&#x8CEA; lymphopoietin &#x306E;&#x751F;&#x7523;&#x306B;&#x4F9D;&#x5B58;&#x3057;&#x3066;&#x3044;&#x305F;&#x3053;&#x3068;&#x3092;&#x898B;&#x3064;&#x3051;&#x305F;&#x3002;&#x3053;&#x306E;&#x7814;&#x7A76;&#x306F;&#x3001;&#x3069;&#x306E;&#x3088;&#x3046;&#x306B;&#x5168;&#x8EAB; Th2 &#x514D;&#x75AB;&#x306E; in vivo &#x3067;&#x306E;&#x8A3C;&#x62E0;&#x306E; Nod &#x523A;&#x6FC0;&#x30B3;&#x30F3;&#x30C6;&#x30AD;&#x30B9;&#x30C8;&#x3067;&#x8A98;&#x5C0E;&#x3055;&#x308C;&#x308B;&#x63D0;&#x4F9B;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x306E;&#x3088;&#x3046;&#x306A;&#x7406;&#x89E3;&#x306F;&#x514D;&#x75AB;&#x30B7;&#x30B9;&#x30C6;&#x30E0;&#x3092;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D6;&#x306A; th1 &#x7D30;&#x80DE;&#x5A92;&#x4ECB;&#x75C5;&#x3001;&#x30AF;&#x30ED;&#x30FC;&#x30F3;&#x75C5;&#x306A;&#x3069;&#x306E;&#x4E2D;&#x306B;&#x30D7;&#x30ED;&#x30B0;&#x30E9;&#x30E0;&#x3057;&#x76F4;&#x3059;&#x3053;&#x3068;&#x304C;&#x6CBB;&#x7642;&#x306E;&#x5408;&#x7406;&#x7684;&#x306A;&#x8A2D;&#x8A08;&#x306B;&#x5F71;&#x97FF;&#x3057;&#x307E;&#x3059;&#x3002;

&#x30CC;&#x30AF;&#x30EC;&#x30AA;&#x30C1;&#x30C9; &#x30AA;&#x30EA;&#x30B4;&#x30E1;&#x30EA;&#x30BC;&#x30FC;&#x30B7;&#x30E7;&#x30F3; &#x30C9;&#x30E1;&#x30A4;&#x30F3;&#x542B;&#x6709;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA; T &#x7D30;&#x80DE;&#x30D8;&#x30EB;&#x30D1;&#x30FC; 2 &#x578B;&#x514D;&#x75AB;&#x7BA1;&#x9593;&#x8CEA;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x6307;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;

&#xB9CE;&#xC740; &#xC5F0;&#xAD6C; T &#xB3C4;&#xC6B0;&#xBBF8; &#xC140; &#xD0C0;&#xC785; 2 (Th2)&#xC758; &#xAC1C;&#xBC1C;&#xC744; &#xAC80;&#xC0AC; &#xD574;&#xC57C; &#xD558;&#xB294; &#xC788;&#xC9C0;&#xB9CC; &#xB2E4;&#xB978; &#xC124;&#xC815;, &#xC801;&#xC751; &#xBA74;&#xC5ED;&#xC774;&#xC774; &#xD314;&#xC758; &#xAC1C;&#xC2DC;&#xB97C; &#xAE30;&#xBCF8; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC5D0;&#xC5D0;&#xC11C; &#xBA74;&#xC5ED; &#xC798; &#xC774;&#xD574; &#xD558;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC; &#xC0AC;&#xC2E4; &#xD56D; &#xC6D0; &#xD50C;&#xB7EC;&#xC2A4; &#xC5B4;&#xB290; &#xB274;&#xD074;&#xB808;&#xC624;&#xD2F0;&#xB4DC; &#xBC14;&#xC778;&#xB529; oligomerization &#xB3C4;&#xBA54;&#xC778;&#xC5D0; &#xD3EC;&#xD568; &#xB41C; &#xB2E8;&#xBC31;&#xC9C8; 1 (Nod1) &#xB610;&#xB294; 2 (Nod2) agonists &#xB4DC;&#xB77C;&#xC774;&#xBE0C; Th2 &#xC720;&#xB3C4; &#xC774;&#xB7EC;&#xD55C; &#xD328;&#xD134; &#xC778;&#xC2DD; &#xC218;&#xC6A9; &#xCCB4; &#xC870;&#xC9C1;&#xC758; Th2 &#xBA74;&#xC5ED; &#xBC18;&#xC751;&#xC758; &#xAC1C;&#xBC1C;&#xC744; &#xC911;&#xC7AC; &#xD558;&#xB294; &#xBC29;&#xBC95;&#xC744; &#xC774;&#xD574; &#xD558;&#xB294; &#xC608;&#xBC29; &#xC811;&#xC885;&#xC744; &#xC545;&#xC6A9;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC;&#xAC00; stromal &#xAD6C;&#xD68D; &#xB0B4; Nod1 &#xBC0F; Nod2 &#xC2DD; &#xC774;&#xD399;&#xD130; CD4(+) Th2 &#xC751;&#xB2F5; &#xBC0F; &#xD2B9;&#xC815; IgG1 &#xD56D; &#xCCB4;&#xC758; &#xC560; &#xBC8C; &#xCE60; &#xD544;&#xC694;&#xB294; &#xACE8; chimeric &#xC0DD;&#xC950;&#xC5D0;&#xC11C; &#xBCF4;&#xC5EC;&#xC90D;&#xB2C8;&#xB2E4;. &#xB300;&#xC870;&#xC801;&#xC73C;&#xB85C;, &#xC218;&#xC9C0;&#xC0C1; &#xC138;&#xD3EC;&#xC5D0; &#xC758;&#xD574; &#xC774;&#xB7EC;&#xD55C; ligands&#xC758; &#xAC10;&#xC9C0; &#xBABB;&#xD55C;&#xB2E4;&#xACE0; Th2 &#xBA74;&#xC5ED;&#xC744; &#xC720;&#xBC1C; &#xD558;&#xAE30;&#xC5D0; &#xCDA9;&#xBD84;&#xC774; &#xC138;&#xD3EC; &#xC751;&#xB2F5;&#xC5D0; &#xAE30;&#xC5EC;. &#xB610;&#xD55C;, &#xC6B0;&#xB9AC; B &#xC138;&#xD3EC;&#xC640; basophils CD4(+) Th2 effector &#xAE30;&#xB2A5;&#xC744; &#xC720;&#xB3C4; &#xD558; &#xACE0; &#xAC1C; &#xB044; &#xB355; ligands&#xC758; &#xC6A9;&#xB7C9;&#xC5D0;&#xB294; &#xC601;&#xD5A5;&#xC744; &#xBBF8;&#xCE58;&#xC9C0; &#xC54A;&#xC558;&#xB2E4; &#xBC18;&#xBA74; CD11c(+) &#xC140;&#xC740; &#xC911;&#xC694; &#xD55C; &#xD56D; &#xC6D0; &#xC81C;&#xC2DC; &#xC138;&#xD3EC;&#xB97C; &#xD655;&#xC778; &#xD588;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB9C8;&#xC9C0;&#xB9C9;&#xC73C;&#xB85C;, &#xC6B0;&#xB9AC;&#xAC00; &#xBC1C;&#xACAC; Nod1 Nod2 &#xD65C;&#xC131;&#xD654;&#xC5D0; &#xB530;&#xB77C; &#xC804;&#xCCB4; Th2 &#xC720;&#xB3C4; stromal &#xC138;&#xD3EC; &#xADF8;&#xB9AC;&#xACE0; &#xC218;&#xC9C0;&#xC0C1; &#xC138;&#xD3EC;&#xC5D0; OX40 ligand costimulatory &#xBD84;&#xC790;&#xC758; &#xC5C5; &#xADDC;&#xC81C;&#xC5D0; &#xC758;&#xD574; &#xB450; thymic &#xAE30;&#xC9C8; lymphopoietin &#xC0DD;&#xC0B0;&#xC5D0; &#xC758;&#xC874; &#xD588;&#xB2E4;. &#xC774; &#xC5F0;&#xAD6C; &#xBC29;&#xBC95;&#xC744; &#xCCB4;&#xACC4;&#xC801; Th2 &#xBA74;&#xC5ED;&#xC758; in vivo &#xC99D;&#xAC70; &#xB044; &#xB355; &#xC790;&#xADF9;&#xC758; &#xB9E5;&#xB77D;&#xC5D0;&#xC11C; &#xC720;&#xB3C4; &#xC81C;&#xACF5; &#xD569;&#xB2C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xC774;&#xD574;&#xB294; &#xD06C; &#xB860; &#xBCD1; &#xB4F1; &#xD558;&#xB294; &#xD65C;&#xC131; Th1 &#xC911;&#xC7AC; &#xC9C8;&#xBCD1;, &#xC911; &#xBA74;&#xC5ED; &#xCCB4;&#xACC4;&#xB97C; &#xC7AC; &#xC124; &#xC815;&#xD560; &#xC218; &#xC788;&#xB294; &#xCE58;&#xB8CC;&#xC81C;&#xC758; &#xD569;&#xB9AC;&#xC801;&#xC778; &#xC124;&#xACC4;&#xB97C; &#xC88C;&#xC6B0;&#xD560; &#xAC83; &#xC774;&#xB2E4;.

&#xB274;&#xD074;&#xB808;&#xC624;&#xD2F0;&#xB4DC; oligomerization &#xB3C4;&#xBA54;&#xC778;&#xC5D0; &#xD3EC;&#xD568; &#xB41C; &#xB2E8;&#xBC31;&#xC9C8; stromal &#xD65C;&#xC131;&#xD654;&#xB97C; &#xD1B5;&#xD574; &#xB3C4;&#xC6B0;&#xBBF8; 2 &#xD615; &#xBA74;&#xC5ED; T &#xC138;&#xD3EC;&#xB97C; &#xC9C0;&#xC2DC;&#xD569;&#xB2C8;&#xB2E4;.

Aunque varios estudios han examinado el desarrollo del tipo de c&eacute;lula T-helper 2 (Th2) inmunidad en diferentes contextos, los mecanismos subyacentes a la iniciaci&oacute;n de este brazo de inmunidad adaptativa no son bien entendidos. Nos explota el hecho de inmunizaci&oacute;n con ant&iacute;geno m&aacute;s bien Oligomerizaci&oacute;n de uni&oacute;n a nucle&oacute;tido que contiene el dominio prote&iacute;nas 1 (Nod1) o 2 (Nod2) agonistas unidades Th2 inducci&oacute;n para comprender c&oacute;mo estos receptores de reconocimiento de patrones median el desarrollo de respuestas sist&eacute;micas de inmune Th2. A continuaci&oacute;n, os mostramos en ratones quim&eacute;ricos de m&eacute;dula &oacute;sea que expresi&oacute;n Nod1 y Nod2 dentro del compartimiento del estroma es necesaria para el cebado de efectoras CD4 Th2 respuestas y anticuerpos IgG1. En contraste, detecci&oacute;n de estos ligandos por c&eacute;lulas dendr&iacute;ticas no era suficiente para inducir inmunidad Th2, aunque estas c&eacute;lulas contribuyen a la respuesta. Por otra parte, determinamos que CD11c(+) c&eacute;lulas eran las c&eacute;lulas presentadoras de ant&iacute;geno cr&iacute;ticas, mientras que los bas&oacute;filos y c&eacute;lulas B no afect&oacute; la capacidad de ligandos de cabeceo para inducir la funci&oacute;n efectora de CD4 Th2. Finalmente, encontramos que completo Th2 inducci&oacute;n al activarse Nod1 y Nod2 depend&iacute;a de producci&oacute;n lymphopoietin estroma t&iacute;mico por las c&eacute;lulas del estroma y la para arriba-regulaci&oacute;n de la mol&eacute;cula coestimuladoras, OX40 Ligando, en c&eacute;lulas dendr&iacute;ticas. Este estudio proporciona evidencia in vivo de forma sist&eacute;mica Th2 inmunidad se induce en el contexto de la estimulaci&oacute;n de cabeceo. Tal entendimiento influir&aacute; en el dise&ntilde;o racional de la terap&eacute;utica que podr&iacute;a reprogramar el sistema inmune durante una enfermedad activa mediada por Th1, como la enfermedad de Crohn.

Prote&iacute;nas de dominio que contienen de Oligomerizaci&oacute;n de nucle&oacute;tido instruir T helper tipo 2 inmunidad a trav&eacute;s de la activaci&oacute;n del estroma.

Invariant natural killer T (iNKT) cells are evolutionarily conserved lipid-reactive T cells that bridge innate and adaptive immune responses. Despite a relatively restricted T-cell receptor (TCR) diversity, these cells respond to a variety of structurally distinct foreign (i.e. microbial or synthetic) as well as host-derived (self-) lipid antigens presented by the CD1d molecule. These multi-tasking lymphocytes are among the first responders in immunity, and produce an impressive array of cytokines and chemokines that can tailor the ensuing immune response. Accordingly, iNKT cells play important functions in autoimmune diseases, cancer, infection and inflammation. These properties make iNKT cells appealing targets in immune-based therapies. Yet, much has to be learned on the mechanisms that allow iNKT cells to produce polarized responses. Responses of iNKT cells are influenced by the direct signals perceived by the cells through their TCRs, as well as by indirect co-stimulatory (and potentially co-inhibitory) cues that they receive from antigen-presenting cells or the local milieu. A decade ago, biochemists and immunologists have started to describe synthetic lipid agonists with cytokine skewing potential, paving a new research avenue in the iNKT cell field. Yet how iNKT cells translate various antigenic signals into distinct functional responses has remained obscure. Recent findings have revealed a unique and innate mode of lipid recognition by iNKT cells, and suggest that both the lipid antigen presented and the diversity of the TCR modulate the strength of CD1d-iNKT TCR interactions. In this review, we focus on novel discoveries on lipid recognition by iNKT cells, and how these findings may help us to design effective strategies to steer iNKT cell responses for immune intervention.

Strategy of lipid recognition by invariant natural killer T cells: 'one for all and all for one'.

La famille Nod-comme des r&eacute;cepteurs (NLR) de mol&eacute;cules de reconnaissance mod&egrave;le intracellulaire joue un r&ocirc;le crucial dans le contr&ocirc;le de l&#39;inflammation par le biais de la modulation des diff&eacute;rentes voies de signalisation, y compris ceux qui d&eacute;pendent de NF-&kappa;B et caspase-1-mediated clivage d&#39;interleukine (IL)-1&beta; et IL-18. Un certain nombre de faible ou de prot&eacute;ines associ&eacute;es &agrave; la NLR ont &eacute;t&eacute; g&eacute;n&eacute;tiquement associ&eacute; &agrave; la susceptibilit&eacute; &agrave; la maladie intestinale inflammatoire (MII), ou maladie de Crohn ou la colite ulc&eacute;reuse. En cons&eacute;quence, des &eacute;tudes r&eacute;centes ont examin&eacute; le r&ocirc;le des prot&eacute;ines NLR dans des mod&egrave;les murins induite par le produit chimique ou induite par la bact&eacute;rie de la colite. Dans cette revue, nous discuterons les associations g&eacute;n&eacute;tiques de NLRs avec IBD et la recherche &agrave; l&#39;aide de la souris d&eacute;ficientes NLR dans des mod&egrave;les diff&eacute;rents de la colite.

R&eacute;cepteurs de type NOD dans le contr&ocirc;le de l&#39;inflammation intestinale.

Die Nod-Like Rezeptor (NLR) Familie intrazellul&auml;re Muster Anerkennung Molek&uuml;le spielt wichtige Rollen bei der Kontrolle der Entz&uuml;ndung durch die Beeinflussung der verschiedenen Signalwege, einschlie&szlig;lich derjenigen abh&auml;ngig von NF-&kappa;B und Caspase-1-vermittelte Spaltung von Interleukin (IL)-1&beta; und IL-18. Eine Anzahl von NLRs oder NLR-assoziierte Proteine sind genetisch mit Anf&auml;lligkeit f&uuml;r entz&uuml;ndliche Darmkrankheit (IBD), Erkrankung oder Colitis ulcerosa oder Morbus Crohn verkn&uuml;pft. J&uuml;ngste Studien haben dementsprechend die Rolle des NLR Proteine in chemisch induziert oder Bakterien induziert murinen Modelle der Kolitis gepr&uuml;ft. In diesem Bericht besprechen wir die genetische Verb&auml;nde der NLRs mit IBD und die Forschung mit NLR-defizienten M&auml;usen in verschiedenen Kolitis-Modelle.

Wink-&auml;hnliche Rezeptoren bei der Kontrolle der Darmentz&uuml;ndung.

&#x70B9;&#x5934;&#x6837;&#x53D7;&#x4F53; (NLR&#xFF09; &#x5BB6;&#x5EAD;&#x7684;&#x80DE;&#x5185;&#x6A21;&#x5F0F;&#x8BC6;&#x522B;&#x5206;&#x5B50;&#x5728;&#x901A;&#x8FC7;&#x4E0D;&#x540C;&#x7684;&#x4FE1;&#x53F7;&#x9014;&#x5F84;&#xFF0C;&#x5305;&#x62EC;&#x90A3;&#x4E9B;&#x4F9D;&#x8D56;&#x4E8E; NF-&kappa; B &#x548C;&#x534A;&#x80F1;&#x6C28;&#x9178;&#x86CB;&#x767D;&#x9176;-1 &#x4ECB;&#x5BFC;&#x7684;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20; (IL) &#x5288;&#x88C2;&#x7684;&#x8C03;&#x8282;&#x708E;&#x75C7;&#x7684;&#x63A7;&#x5236;&#x4E2D;&#x626E;&#x6F14;&#x5173;&#x952E;&#x89D2;&#x8272;-1&beta; &#x548C; IL-18&#x3002;NLRs &#x6216; NLR &#x76F8;&#x5173;&#x86CB;&#x767D;&#x7684;&#x6570;&#x91CF;&#x5DF2;&#x4E0E;&#x708E;&#x75C7;&#x6027;&#x80A0;&#x75C5; (IBD) &#x6613;&#x611F;&#x6027;&#x3001; &#x8981;&#x4E48;&#x514B;&#x7F57;&#x6069;&#x75C5;&#x6216;&#x6E83;&#x75A1;&#x6027;&#x7ED3;&#x80A0;&#x708E;&#x57FA;&#x56E0;&#x76F8;&#x5173;&#x8054;&#x3002;&#x56E0;&#x6B64;&#xFF0C;&#x6700;&#x8FD1;&#x7684;&#x7814;&#x7A76;&#x5BA1;&#x67E5;&#x4E86;&#x5316;&#x5B66;&#x7269;&#x8BF1;&#x5BFC;&#x6216;&#x7EC6;&#x83CC;&#x6240;&#x81F4;&#x7684;&#x5C0F;&#x9F20;&#x6A21;&#x578B;&#x7684;&#x7ED3;&#x80A0;&#x708E; NLR &#x86CB;&#x767D;&#x8D28;&#x7684;&#x4F5C;&#x7528;&#x3002;&#x5728;&#x8FD9;&#x6B21;&#x5BA1;&#x67E5;&#xFF0C;&#x6211;&#x4EEC;&#x5C06;&#x8BA8;&#x8BBA;&#x7684;&#x9057;&#x4F20;&#x5173;&#x8054;&#x7684; NLRs &#x708E;&#x75C7;&#x6027;&#x80A0;&#x75C5;&#x53CA;&#x5728;&#x4E0D;&#x540C;&#x7ED3;&#x80A0;&#x708E;&#x6A21;&#x578B;&#x4E2D;&#x4F7F;&#x7528; NLR &#x7F3A;&#x9677;&#x5C0F;&#x9F20;&#x7684;&#x7814;&#x7A76;&#x3002;

&#x70B9;&#x5934;&#x6837;&#x53D7;&#x4F53;&#x5728;&#x80A0;&#x9053;&#x708E;&#x75C7;&#x7684;&#x63A7;&#x5236;&#x3002;

The Nod-like receptor (NLR) family of intracellular pattern recognition molecules plays critical roles in the control of inflammation through the modulation of different signalling pathways, including those dependent on NF-ÎºB and caspase-1-mediated cleavage of interleukin (IL)-1Î² and IL-18. A number of NLRs or NLR-associated proteins have been genetically associated with susceptibility to inflammatory bowel disease (IBD), either Crohn's disease or ulcerative colitis. Accordingly, recent studies have examined the role of NLR proteins in chemical-induced or bacteria-induced murine models of colitis. In this review, we will discuss the genetic associations of NLRs with IBD and the research using NLR-deficient mice in different colitis models.

Nod-like receptors in the control of intestinal inflammation.

La famiglia del recettore (NLR) Nod-come di molecole di riconoscimento di pattern intracellulare svolge ruoli critici nel controllo dell&#39;infiammazione attraverso la modulazione delle vie di segnalazione diversi, compresi quelli dipendente da NF-&kappa;B e caspase-1-mediata scissione dell&#39;interleuchina (IL)-1 &beta; e IL-18. Un certo numero di NLRs o NLR-associated proteins &egrave; state geneticamente associato con la suscettibilit&agrave; alle malattie infiammatorie intestinali (IBD), la malattia sia di Crohn o la colite ulcerosa. Di conseguenza, studi recenti hanno esaminato il ruolo delle proteine NLR in modelli murini indotta da sostanze chimiche o batteri-indotta della colite. In questa recensione, si discuter&agrave; delle associazioni genetiche del NLRs con IBD e la ricerca utilizzando il mouse NLR-carenti in modelli diversi di colite.

Cenno-come recettori nel controllo di infiammazione intestinale.

&#x7D30;&#x80DE;&#x5185;&#x30D1;&#x30BF;&#x30FC;&#x30F3;&#x8A8D;&#x8B58;&#x5206;&#x5B50;&#x306E; Nod &#x306E;&#x3088;&#x3046;&#x306A;&#x53D7;&#x5BB9;&#x4F53; &#xFF08;NLR) &#x30D5;&#x30A1;&#x30DF;&#x30EA;&#x30FC; NF-&kappa; &#x304A;&#x3088;&#x3073;&#x5207;&#x65AD;&#x30AB;&#x30B9;&#x30D1;&#x30FC;&#x30BC; 1 &#x3092;&#x4ECB;&#x3057;&#x305F;&#x30A4;&#x30F3;&#x30BF;&#x30FC;&#x30ED;&#x30A4;&#x30AD;&#x30F3; (IL) &#x306E;&#x4E0A;&#x306B;&#x4F9D;&#x5B58;&#x3082;&#x542B;&#x3081;&#x3001;&#x5225;&#x306E;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x7D4C;&#x8DEF;&#x306E;&#x5909;&#x8ABF;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x708E;&#x75C7;&#x306E;&#x30B3;&#x30F3;&#x30C8;&#x30ED;&#x30FC;&#x30EB;&#x3067;&#x91CD;&#x8981;&#x306A;&#x5F79;&#x5272;&#x3092;&#x679C;&#x305F;&#x3057;&#x3066;&#x3044;&#x308B;-1 &beta; &#x304A;&#x3088;&#x3073; IL 18&#x3002;NLRs &#x307E;&#x305F;&#x306F; NLR &#x95A2;&#x9023;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306E;&#x6570;&#x306F;&#x3001;&#x708E;&#x75C7;&#x6027;&#x8178;&#x75BE;&#x60A3; &#xFF08;IBD&#xFF09; &#x611F;&#x53D7;&#x6027;&#x3001;&#x3069;&#x3061;&#x3089;&#x304B; Crohn &#x75C5;&#x3084;&#x6F70;&#x760D;&#x6027;&#x5927;&#x8178;&#x708E;&#x3068;&#x907A;&#x4F1D;&#x7684;&#x306B;&#x95A2;&#x9023;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;&#x6700;&#x8FD1;&#x306E;&#x7814;&#x7A76;&#x306F; NLR &#x86CB;&#x767D;&#x8CEA;&#x5316;&#x5B66;&#x8A98;&#x767A;&#x307E;&#x305F;&#x306F;&#x7D30;&#x83CC;&#x8A98;&#x5C0E;&#x6027;&#x5927;&#x8178;&#x708E;&#x306E;&#x30DE;&#x30A6;&#x30B9;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x306E;&#x5F79;&#x5272;&#x3092;&#x691C;&#x8A0E;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x306E;&#x30EC;&#x30D3;&#x30E5;&#x30FC;&#x3067;&#x306F;&#x3001;NLRs IBD &#x3068;&#x7570;&#x306A;&#x308B;&#x5927;&#x8178;&#x708E;&#x30E2;&#x30C7;&#x30EB;&#x306B;&#x304A;&#x3051;&#x308B; NLR &#x6B20;&#x640D;&#x30DE;&#x30A6;&#x30B9;&#x3092;&#x7528;&#x3044;&#x305F;&#x7814;&#x7A76;&#x3068;&#x907A;&#x4F1D;&#x306E;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x306B;&#x3064;&#x3044;&#x3066;&#x8AAC;&#x660E;&#x3057;&#x307E;&#x3059;&#x3002;

Nod &#x69D8;&#x53D7;&#x5BB9;&#x4F53;&#x8178;&#x306E;&#x708E;&#x75C7;&#x306E;&#x30B3;&#x30F3;&#x30C8;&#x30ED;&#x30FC;&#x30EB;&#x3002;

&#xC138;&#xD3EC;&#xB0B4; &#xD328;&#xD134; &#xC778;&#xC2DD; &#xBD84;&#xC790;&#xC758; &#xB044; &#xB355; &#xC784; &#xAC19;&#xC774; &#xC218;&#xC6A9; &#xCCB4; (NLR) &#xAC00;&#xC871; NF &kappa;B &#xBC0F; &#xC778;&#xD130; &#xB8E8; &#xD0A8; (IL)&#xC758; &#xBD84;&#xC5F4; caspase 1 &#xC911;&#xC7AC;&#xC5D0; &#xC758;&#xC874; &#xD3EC;&#xD568; &#xD558; &#xC5EC; &#xB2E4;&#xB978; &#xC2E0;&#xD638; &#xD1B5;&#xB85C;&#xC758; &#xBCC0;&#xC870;&#xB97C; &#xD1B5;&#xD574; &#xC5FC;&#xC99D; &#xCEE8;&#xD2B8;&#xB864;&#xC5D0; &#xC911;&#xC694; &#xD55C; &#xC5ED;&#xD560; &#xB2F4;&#xB2F9;-1&beta; &#xBC0F; IL-18. &#xB2E4;&#xC591; &#xD55C; NLRs &#xB610;&#xB294; NLR &#xAD00;&#xB828; &#xB2E8;&#xBC31;&#xC9C8; &#xC720;&#xC804;&#xC790; &#xC120; &#xB3D9;&#xC801;&#xC778; &#xC7A5; &#xC9C8;&#xBCD1; (IBD)&#xC5D0;, &#xC5B4;&#xB290; Crohn&#xC758; &#xC9C8;&#xBCD1; &#xB610;&#xB294; &#xADA4; &#xC591;&#xC131; &#xB300; &#xC7A5; &#xC5FC;&#xC5D0; &#xC5F0;&#xAD00; &#xB41C;. &#xC774; &#xB530;&#xB77C; &#xCD5C;&#xADFC; &#xC5F0;&#xAD6C; colitis&#xC758; &#xD654;&#xD559; &#xC720;&#xB3C4; &#xB610;&#xB294; &#xBC15;&#xD14C;&#xB9AC;&#xC544; &#xC720;&#xB3C4; murine &#xBAA8;&#xB378;&#xC5D0;&#xC11C; NLR &#xB2E8;&#xBC31;&#xC9C8;&#xC758; &#xC5ED;&#xD560;&#xC744; &#xC0B4;&#xD3B4;&#xBCF4;&#xC558;&#xB2E4;. &#xC774; &#xAC80;&#xD1A0; IBD NLR &#xBD88;&#xCDA9;&#xBD84; &#xD55C; &#xB9C8;&#xC6B0;&#xC2A4;&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xB2E4;&#xB978; colitis &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xC5F0;&#xAD6C;&#xC640; Nlrs&#xC758; &#xC720;&#xC804; &#xC5F0;&#xACB0;&#xC744; &#xD558;&#xACA0;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xB044; &#xB355; &#xAC19;&#xC740; &#xC218;&#xC6A9; &#xCCB4; &#xC7A5; &#xC5FC;&#xC99D;&#xC758; &#xC81C;&#xC5B4;.

La familia de Nod-like receptor (NLR) de mol&eacute;culas de reconocimiento de patr&oacute;n intracelular juega un papel cr&iacute;tico en el control de la inflamaci&oacute;n a trav&eacute;s de la modulaci&oacute;n de diferentes v&iacute;as de se&ntilde;alizaci&oacute;n, los que dependen de la NF-&kappa;B y escote caspasa-1-mediada de la interleucina (IL) incluyendo-1&beta; e IL-18. Un n&uacute;mero de NLRs o prote&iacute;nas asociadas NLR ha sido gen&eacute;ticamente asociado con la susceptibilidad a la enfermedad inflamatoria intestinal (EII), enfermedad o Crohn o colitis ulcerativa. En consecuencia, los estudios recientes han examinado el papel de las prote&iacute;nas NLR en modelos murinos inducida por qu&iacute;micos o inducida por bacterias de la colitis. En esta revisi&oacute;n, discutiremos las asociaciones gen&eacute;ticas de NLRs con EII y la investigaci&oacute;n en ratones deficientes en NLR de modelos diferentes de la colitis.

Receptores de Nod-like en el control de la inflamaci&oacute;n intestinal.

Invariant NKT (iNKT) cells act at the crossroad between innate and adaptive immunity and are important players in the defense against microbial pathogens. iNKT cells can detect pathogens that trigger innate receptors (e.g., TLRs, Rig-I, Dectin-1) within APCs, with the consequential induction of CD1d-mediated Ag presentation and release of proinflammatory cytokines. We show that the cytosolic peptidoglycan-sensing receptors Nod1 and Nod2 are necessary for optimal IFN-γ production by iNKT cells, as well as NK cells. In the absence of Nod1 and Nod2, iNKT cells had a blunted IFN-γ response following infection by Salmonella enterica serovar Typhimurium and Listeria monocytogenes. For Gram-negative bacteria, we reveal a synergy between Nod1/2 and TLR4 in dendritic cells that potentiates IL-12 production and, ultimately, activates iNKT cells. These findings suggest that multiple innate pathways can cooperate to regulate iNKT cell activation during bacterial infection.

Nod1 and Nod2 enhance TLR-mediated invariant NKT cell activation during bacterial infection.

Females exhibit more robust Th1 responses than males. Our previous work suggested that this sex disparity is a consequence of higher activity of the androgen-induced gene peroxisome proliferator-activated receptor α (PPARα) in male CD4(+) T cells. The objective of this study was to elucidate the cellular and molecular mechanism of how PPARα inhibits Th1 responses in male mice. In this study, we found that PPARα functions within CD4(+) and CD8(+) T lymphocytes and NKT cells to negatively regulate IFN-γ responses in male mice and identified Ifng as the gene target of PPARα repression. Treatment of male CD4(+) T cells with the PPARα agonist fenofibrate induced the recruitment of PPARα and the nuclear receptor-interacting protein, nuclear receptor corepressor 1, to specific cis-regulatory elements in the Ifng locus. This recruitment associated with reduced histone acetylation at these sites. Knockdown of nuclear receptor corepressor 1 in primary male T cells abolished the effect of fenofibrate in reducing IFN-γ production. In contrast, treatment of male T cells with IS001, a novel antagonist of PPARα, increased Ifng gene expression and histone acetylation across the Ifng locus. Finally, we investigated the effects of IS001 on IFN-γ responses in mice during infection with the Th1-associated pathogen Listeria monocytogenes and observed that IS001 enhanced IFN-γ production by NKT, CD4(+), and CD8(+) T cells and improved the survival of male, but not female, mice. Our findings provide a novel mechanism of why IFN-γ responses are more robust in females and introduce a small-molecule IS001 that can be used to enhance Th1 immunity in males.

Antagonizing Peroxisome Proliferator-Activated Receptor α Activity Selectively Enhances Th1 Immunity in Male Mice.

NKT cells are unconventional T cells that respond to self and microbe-derived lipid and glycolipid Ags presented by the CD1d molecule. Invariant NKT (iNKT) cells influence immune responses in numerous diseases. Although only a few studies have examined their role during intestinal inflammation, it appears that iNKT cells protect from Th1-mediated inflammation but exacerbate Th2-mediated inflammation. Studies using iNKT cell-deficient mice and chemically induced dextran sodium sulfate (DSS) colitis have led to inconsistent results. In this study, we show that CD1d-deficient mice, which lack all NKT cells, harbor an altered intestinal microbiota that is associated with exacerbated intestinal inflammation at steady-state and following DSS treatment. This altered microbiota, characterized by increased abundance of the bacterial phyla Proteobacteria, Deferribacteres, and TM7, among which the mucin-eating Mucispirillum, as well as members of the genus Prevotella and segmented filamentous bacteria, was transmissible upon fecal transplant, along with the procolitogenic phenotype. Our results also demonstrate that this proinflammatory microbiota influences iNKT cell function upon activation during DSS colitis. Collectively, alterations of the microbiota have a major influence on colitis outcome and therefore have to be accounted for in such experimental settings and in studies focusing on iNKT cells.

Thirumahal Selvanantham

Department of Immunology

University of Toronto

Experimental Infection with Listeria monocytogenes as a Model for Studying Host Interferon-γ Responses

Thirumahal Selvanantham

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Immunology

University of Toronto

Experimental Infection with Listeria monocytogenes as a Model for Studying Host Interferon-γ Responses

Department of Immunology