calcification-vascular-smooth-muscle-cells-imaging-aortic

Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation

Cardiovascular disease is the leading cause of morbidity and mortality in the world.  Atherosclerotic plaques, consisting of lipid-laden macrophages and ...

Massachusetts General Hospital

Harvard Medical School

Sepsis is initiated by interactions between microbial products and host inflammatory cells. Toll-like receptors (TLRs) are central innate immune mediators of sepsis that recognize different components of microorganisms. Peptidoglycan-associated lipoprotein (PAL) is a ubiquitous gram-negative bacterial outer-membrane protein that is shed by bacteria into the circulation of septic animals. We explored the inflammatory effects of purified PAL and of a naturally occurring form of PAL that is shed into serum. PAL is released into human serum by Escherichia coli bacteria in a form that induces cytokine production by macrophages and is tightly associated with lipopolysaccharide (LPS). PAL activates inflammation through TLR2. PAL and LPS synergistically activate macrophages. These data suggest that PAL may play an important role in the pathogenesis of sepsis and imply that physiologically relevant PAL and LPS are shed into serum and act in concert to initiate inflammation in sepsis.

Bacterial peptidoglycan-associated lipoprotein: a naturally occurring toll-like receptor 2 agonist that is shed into serum and has synergy with lipopolysaccharide.

TLRs sense components of microorganisms and are critical host mediators of inflammation during infection. Different TLR agonists can profoundly alter inflammatory effects of one another, and studies suggest that the sequence of exposure to TLR agonists may importantly impact on responses during infection. We tested the hypothesis that synergy, priming, and tolerance between TLR agonists follow a pattern that can be predicted based on differential engagement of the MyD88-dependent (D) and the MyD88-independent (I) intracellular signaling pathways. Inflammatory effects of combinations of D and I pathway agonists were quantified in vivo and in vitro. Experiments used several D-specific agonists, an I-specific agonist (poly(I:C)), and LPS, which acts through both the D and I pathways. D-specific agonists included: peptidoglycan-associated lipoprotein, Pam3Cys, flagellin, and CpG DNA, which act through TLR2 (peptidoglycan-associated lipoprotein and Pam3Cys), TLR5, and TLR9, respectively. D and I agonists were markedly synergistic in inducing cytokine production in vivo in mice. All of the D-specific agonists were synergistic with poly(I:C) in vitro in inducing TNF and IL-6 production by mouse bone marrow-derived macrophages. Pretreatment of bone marrow-derived macrophages with poly(I:C) led to a primed response to subsequent D-specific agonists and vice versa, as indicated by increased cytokine production, and increased NF-kappaB translocation. Pretreatment with a D-specific agonist augmented LPS-induced IFN-beta production. All D-specific agonists induced tolerance to one another. Thus, under the conditions studied here, simultaneous and sequential activation of both the D and I pathways causes synergy and priming, respectively, and tolerance is induced by agonists that act through the same pathway.

MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists.

Multiple older studies report that immunoglobulin directed to rough mutant bacteria, such as E. coli J5, provides broad protection against challenge with heterologous strains of Gram-negative bacteria. This protection was initially believed to occur through binding of immunoglobulin to bacterial lipopolysaccharide (LPS). However, hundreds of millions of dollars have been invested in attempting to develop clinically-effective anti-LPS monoclonal antibodies without success, and no study has shown that IgG from this antiserum binds LPS. Identification of the protective mechanism would facilitate development of broadly protective human monoclonal antibodies for treating sepsis. IgG from this antiserum binds 2 bacterial outer membrane proteins: murein lipoprotein (MLP) and peptidoglycan-associated lipoprotein (PAL). Both of these outer membrane proteins are highly conserved, have lipid domains that are anchored in the bacterial membrane, are shed from bacteria in blebs together with LPS, and activate cells through Toll-like receptor 2. Our goal in the current work was to determine if passive immunization directed to MLP and PAL protects mice from Gram-negative sepsis. Neither monoclonal nor polyclonal IgG directed to MLP or PAL conferred survival protection in 3 different models of sepsis: cecal ligation and puncture, an infected burn model, and an infected fibrin clot model mimicking peritonitis. Our results are not supportive of the hypothesis that either anti-MLP or anti-PAL IgG are the protective antibodies in the previously described anti-rough mutant bacterial antisera. These studies suggest that a different mechanism of protection is involved.

Passive immunization to outer membrane proteins MLP and PAL does not protect mice from sepsis.

&#x867D;&#x7136;&#x5FC3;&#x529F;&#x80FD;&#x4E0D;&#x5168;&#x7684;&#x8113;&#x6BD2;&#x75C7;&#x53D1;&#x75C5;&#x673A;&#x5236;&#x4E2D;&#x53D1;&#x6325;&#x7740;&#x91CD;&#x8981;&#x4F5C;&#x7528;&#xFF0C;&#x9020;&#x6210;&#x8113;&#x6BD2;&#x75C7;&#x60A3;&#x8005;&#x7684;&#x5FC3;&#x810F;&#x529F;&#x80FD;&#x969C;&#x788D;&#x7684;&#x673A;&#x5236;&#x4ECD;&#x7136;&#x77E5;&#x4E4B;&#x751A;&#x5C11;&#x3002;&#x8102;&#x7EC6;&#x83CC;&#x80BD;&#x805A;&#x7CD6;&#x76F8;&#x5173;&#x86CB;&#x767D; (PAL) &#x7684;&#x9769;&#x5170;&#x9634;&#x6027;&#x83CC;&#x5916;&#x819C;&#x86CB;&#x767D;&#x6700;&#x8FD1;&#x88AB;&#x53D1;&#x73B0;&#x5C06;&#x88AB;&#x91CA;&#x653E;&#x5230;&#x8840;&#x6DB2;&#x91CC;&#x8113;&#x6BD2;&#x75C7;&#x548C;&#x5C0F;&#x9F20;&#x5F15;&#x8D77;&#x708E;&#x75C7;&#x548C;&#x6B7B;&#x4EA1;&#x3002;&#x672C;&#x7814;&#x7A76;&#x8BC4;&#x4F30;&#x4E86; PAL &#x5BF9;&#x5FC3;&#x808C;&#x7EC6;&#x80DE;&#x529F;&#x80FD;&#x7684;&#x5F71;&#x54CD;&#x548C;&#x5176;&#x5FC3;&#x808C;&#x7EC6;&#x80DE;&#x5185;&#x7684;&#x4FE1;&#x53F7;&#x8F6C;&#x5BFC;&#x3002;

Toll &#x6837;&#x53D7;&#x4F53; 2 &#x6FC0;&#x6D3B;&#x7EC6;&#x83CC;&#x76F8;&#x5173;&#x80BD;&#x805A;&#x7CD6;&#x8102;&#x86CB;&#x767D;&#x6FC0;&#x6D3B;&#x5FC3;&#x808C;&#x7EC6;&#x80DE;&#x708E;&#x75C7;&#x53CA;&#x6536;&#x7F29;&#x529F;&#x80FD;&#x969C;&#x788D;&#x3002;

Although cardiac dysfunction plays an important role in the pathogenesis of sepsis, the mechanisms that underlie cardiac dysfunction in sepsis remain poorly understood. Bacterial peptidoglycan-associated lipoprotein (PAL), an outer-membrane protein of Gram-negative bacteria, was recently found to be released into the bloodstream in sepsis and to cause inflammation and death in mice. The present studies assessed the effects of PAL on cardiomyocyte function and its signal transduction in cardiomyocytes.

Toll-like receptor 2 activation by bacterial peptidoglycan-associated lipoprotein activates cardiomyocyte inflammation and contractile dysfunction.

Bien que la dysfonction cardiaque joue un r&#xF4;le important dans la pathogen&#xE8;se de l&#x26;#39;infection, les m&#xE9;canismes qui sous-tendent la dysfonction cardiaque dans le sepsis sont encore mal compris. Bact&#xE9;rienne associ&#xE9;e &#xE0; un peptidoglycane lipoprot&#xE9;ine (PAL), une prot&#xE9;ine de la membrane externe des bact&#xE9;ries Gram-n&#xE9;gatives, a r&#xE9;cemment &#xE9;t&#xE9; trouv&#xE9;e d&#x26;#39;&#xEA;tre lib&#xE9;r&#xE9;s dans la circulation sanguine dans le sepsis et de provoquer une inflammation et la mort chez les souris. Les pr&#xE9;sentes &#xE9;tudes ont &#xE9;valu&#xE9; les effets de PAL sur la fonction des cardiomyocytes et sa transduction du signal dans les cardiomyocytes.

Toll-like Receptor 2 Activation par bact&#xE9;rienne associ&#xE9;e &#xE0; un peptidoglycane lipoprot&#xE9;ines Active inflammation et la dysfonction contractile des cardiomyocytes

Obwohl kardialer Dysfunktion eine wichtige Rolle in der Pathogenese von Sepsis spielt, bleiben die Mechanismen, die kardiale Dysfunktion bei Sepsis zugrunde liegen, weitgehend unverstanden. Bakterielle Peptidoglycan-assoziierte Lipoprotein (PAL), ein Protein, das &auml;u&szlig;ere Membran von gramnegativen Bakterien, wurde vor kurzem in den Blutkreislauf in Sepsis freigegeben werden und zu Entz&uuml;ndungen und zum Tode f&uuml;hren bei M&auml;usen gefunden. Die vorliegenden Studien bewertet die Auswirkungen von PAL auf Cardiomyocyte-Funktion und die Signaltransduktion in den Cardiomyocytes.

Toll-Like-Rezeptor 2 Aktivierung durch bakterielle Peptidoglycan-assoziierte Lipoprotein aktiviert Cardiomyocyte Entz&uuml;ndung und kontraktilen Dysfunktion.

Sebbene la disfunzione cardiaca gioca un ruolo importante nella patogenesi della sepsi, i meccanismi che sottendono alla disfunzione cardiaca nella sepsi rimangono scarsamente comprensibili. Batterica lipoproteina associata peptidoglicano (PAL), una proteina della membrana esterna dei batteri Gram-negativi, recentemente &egrave; stato trovato per essere rilasciato nel flusso sanguigno in sepsi e causare infiammazione e morte nei topi. Gli studi presenti ha valutato gli effetti del PAL sulla funzione del cardiomyocyte e la trasduzione del segnale nei cardiomyocytes.

Attivazione del recettore toll-like 2 da lipoproteine batteriche peptidoglicano associato attiva cardiomyocyte infiammazione e disfunzione contrattile.

&#x5FC3;&#x6A5F;&#x80FD;&#x969C;&#x5BB3;&#x3001;&#x6557;&#x8840;&#x75C7;&#x306E;&#x75C5;&#x56E0;&#x306B;&#x91CD;&#x8981;&#x306A;&#x5F79;&#x5272;&#x3092;&#x679C;&#x305F;&#x3057;&#x3066;&#x3044;&#x308B;&#x304C;&#x3001;&#x6557;&#x8840;&#x75C7;&#x306B;&#x5FC3;&#x6A5F;&#x80FD;&#x969C;&#x5BB3;&#x306E;&#x6839;&#x5E95;&#x306B;&#x3042;&#x308B;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x306F;&#x3088;&#x304F;&#x308F;&#x304B;&#x3063;&#x3066;&#x3044;&#x306A;&#x3044;&#x307E;&#x307E;&#x3067;&#x3059;&#x3002;&#x7D30;&#x83CC;&#x306E;&#x30DA;&#x30D7;&#x30C1;&#x30C9;&#x30B0;&#x30EA;&#x30AB;&#x30F3;&#x95A2;&#x9023;&#x30EA;&#x30DD;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#xFF08;PAL&#xFF09;&#x3001;&#x30B0;&#x30E9;&#x30E0;&#x9670;&#x6027;&#x83CC;&#x306E;&#x5916;&#x819C;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306F;&#x3001;&#x6700;&#x8FD1;&#x3001;&#x6557;&#x8840;&#x75C7;&#x3067;&#x8840;&#x6D41;&#x306B;&#x653E;&#x51FA;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3053;&#x3068;&#x304C;&#x308F;&#x304B;&#x3063;&#x305F;&#x3068;&#x3057;&#x305F;&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x708E;&#x75C7;&#x304A;&#x3088;&#x3073;&#x6B7B;&#x3092;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3059;&#x3002;&#x73FE;&#x5728;&#x306E;&#x7814;&#x7A76;&#x3067;&#x306F;&#x3001;&#x5FC3;&#x7B4B;&#x7D30;&#x80DE;&#x306B;&#x304A;&#x3051;&#x308B;&#x5FC3;&#x7B4B;&#x7D30;&#x80DE;&#x6A5F;&#x80FD;&#x3068;&#x305D;&#x306E;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x306B;PAL&#x306E;&#x52B9;&#x679C;&#x3092;&#x8A55;&#x4FA1;&#x3057;&#x305F;&#x3002;

&#x7D30;&#x83CC;&#x306E;&#x30DA;&#x30D7;&#x30C1;&#x30C9;&#x30B0;&#x30EA;&#x30AB;&#x30F3;&#x95A2;&#x9023;&#x30EA;&#x30DD;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306B;&#x3088;&#x308B;Toll&#x69D8;&#x53D7;&#x5BB9;&#x4F53;2&#x306E;&#x6D3B;&#x6027;&#x5316;&#x306F;&#x5FC3;&#x7B4B;&#x708E;&#x75C7;&#x3068;&#x53CE;&#x7E2E;&#x4E0D;&#x5168;&#x3092;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D6;&#x306B;&#x3057;&#x307E;&#x3059;

&#xC2EC;&#xC7A5; &#xBD80;&#xC804; &#xD328; &#xD608; &#xC99D;&#xC758; &#xBCD1; &#xC778;&#xC5D0; &#xC911;&#xC694; &#xD55C; &#xC5ED;&#xD560;&#xC744;, &#xBE44;&#xB85D; &#xD328; &#xD608; &#xC99D;&#xC5D0; &#xC2EC;&#xC7A5; &#xBD80;&#xC804;&#xC758; &#xAE30;&#xCD08;&#xAC00; &#xB418;&#xB294; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xC81C;&#xB300;&#xB85C; &#xC774;&#xD574; &#xB0A8;&#xC544; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xD328; &#xD608; &#xC99D;&#xC5D0;&#xC11C; &#xD608; &#xB958;&#xB85C; &#xBC1C;&#xD45C; &#xD558; &#xACE0; &#xC6D0;&#xC778;&#xC774; &#xC5FC;&#xC99D;&#xACFC; &#xC8FD;&#xC74C; &#xC0DD;&#xC950;&#xC5D0;&#xC11C; &#xC138;&#xADE0;&#xC131; peptidoglycan &#xAD00;&#xB828; &#xC9C0; &#xB2E8;&#xBC31; (PAL), &#xADF8;&#xB78C; &#xC74C;&#xC131; &#xC138;&#xADE0;&#xC758; &#xBC14;&#xAE65;&#xCABD; &#xB9C9; &#xB2E8;&#xBC31;&#xC9C8; &#xCD5C;&#xADFC; &#xBC1D;&#xD600;&#xC84C;&#xB2E4;. &#xD604;&#xC7AC; &#xC5F0;&#xAD6C; cardiomyocyte &#xD568;&#xC218;&#xC5D0; PAL&#xC758; &#xD6A8;&#xACFC; &#xBC0F; cardiomyocytes&#xC5D0; &#xC2E0;&#xD638; &#xC804;&#xB2EC;&#xC758; &#xD3C9;&#xAC00;.

&#xC138;&#xADE0;&#xC131; peptidoglycan &#xAD00;&#xB828; &#xB2E8;&#xBC31;&#xC5D0;&#xC758; &#xD55C; &#xC218;&#xC6A9; &#xCCB4; &#xD1B5;&#xD589;&#xC138; &#xAC19;&#xC774; 2 &#xD65C;&#xC131;&#xD654; &#xD65C;&#xC131;&#xD654; cardiomyocyte &#xC5FC;&#xC99D;&#xACFC; &#xC218;&#xCD95; &#xBD80;&#xC804;.

Aunque la disfunci&#xF3;n cardiaca juega un papel importante en la patogenia de la sepsis, los mecanismos que subyacen a la disfunci&#xF3;n card&#xED;aca en la sepsis siguen siendo poco conocidos. Bacteriana asociada a la lipoprote&#xED;na de peptidoglicano (PAL), una prote&#xED;na de membrana externa de bacterias Gram-negativas, se ha descubierto recientemente que se liberan en el torrente sangu&#xED;neo en la sepsis y para causar la inflamaci&#xF3;n y la muerte en ratones. El presente estudio evalu&#xF3; los efectos del PAL en funci&#xF3;n de los cardiomiocitos y su transducci&#xF3;n de se&#xF1;ales en los cardiomiocitos.

Toll-like receptor 2 Activaci&#xF3;n por peptidoglicano bacteriana asociada a lipoprote&#xED;na Activa la inflamaci&#xF3;n y la disfunci&#xF3;n contr&#xE1;ctil cardiomiocitos

Activaci&oacute;n inmune es una caracter&iacute;stica importante del virus de inmunodeficiencia humana tipo 1 (VIH-1) infecci&oacute;n y un fuerte factor pron&oacute;stico de progresi&oacute;n de la enfermedad del VIH-1. Los mecanismos subyacentes a la activaci&oacute;n inmune en la infecci&oacute;n por VIH-1 viremic, sin embargo, no se entienden completamente. Aqu&iacute; mostramos que, despu&eacute;s de la iniciaci&oacute;n de la terapia antiretroviral altamente activa, la disminuci&oacute;n inmediata de la activaci&oacute;n inmune est&aacute; estrechamente relacionado con la reducci&oacute;n de la viremia del VIH-1, que sugiere una contribuci&oacute;n directa del VIH-1 s&iacute; mismo a la activaci&oacute;n inmune. Para proponer un mecanismo, demostramos que el ARN monocatenario del VIH-1 codifica m&uacute;ltiples Uridina ricos Toll-like receptor 7/8 (TLR7/8) ligandos que inducen c&eacute;lulas dendr&iacute;ticas fuerte de MyD88 dependiente plasmacytoid y activaci&oacute;n de monocitos, as&iacute; como la activaci&oacute;n de c&eacute;lulas T celular del accesorio dependiente. Ligandos TLR codificada en VIH-1 por lo tanto, pueden, contribuyen directamente a la activaci&oacute;n inmune observada durante la infecci&oacute;n por VIH-1 viremic. Estos datos proporcionan una justificaci&oacute;n inicial para inhibir la v&iacute;a TLR para reducir directamente la activaci&oacute;n inmune cr&oacute;nica inducida por VIH-1 y la patogenesia inmune asociada.

MyD88 dependiente activaci&oacute;n inmune mediada por ligandos de virus de inmunodeficiencia humana tipo 1-codificado Toll-like receptor.

&#x514D;&#x75AB;&#x6FC0;&#x6D3B;&#x662F;&#x4EBA;&#x7C7B;&#x514D;&#x75AB;&#x7F3A;&#x9677;&#x75C5;&#x6BD2;&#x7684;&#x4E3B;&#x8981;&#x7279;&#x5F81;&#x952E;&#x5165; 1 &#xFF08;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x578B;&#xFF09; &#x611F;&#x67D3;&#x548C;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x75BE;&#x75C5;&#x8FDB;&#x5C55;&#x7684;&#x4E00;&#x4E2A;&#x5F3A;&#x9884;&#x540E;&#x56E0;&#x7D20;&#x3002;&#x5E95;&#x5C42;&#x7684;&#x673A;&#x5236;&#x5BFC;&#x81F4;&#x514D;&#x75AB;&#x6D3B;&#x5316;&#x7684; viremic-1 &#x827E;&#x6ECB;&#x75C5;&#x6BD2;&#x611F;&#x67D3;&#xFF0C;&#x4F46;&#x662F;&#xFF0C;&#x8FD8;&#x4E0D;&#x5145;&#x5206;&#x4E86;&#x89E3;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x663E;&#x793A;&#xFF0C;&#x542F;&#x52A8;&#x4E4B;&#x540E;&#x7684;&#x9AD8;&#x6D3B;&#x6027;&#x6297;&#x9006;&#x8F6C;&#x5F55;&#x75C5;&#x6BD2;&#x7597;&#x6CD5;&#xFF0C;&#x514D;&#x75AB;&#x6FC0;&#x6D3B;&#x7ACB;&#x5373;&#x4E0B;&#x964D;&#x662F;&#x4E0E;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x75C5;&#x6BD2;&#x8840;&#x75C7;&#xFF0C;&#x8FD9;&#x8868;&#x660E;&#x5BF9;&#x514D;&#x75AB;&#x6FC0;&#x6D3B;&#x5BF9;&#x81EA;&#x5DF1; 1 &#x827E;&#x6ECB;&#x75C5;&#x6BD2;&#x7684;&#x76F4;&#x63A5;&#x8D21;&#x732E;&#x7684;&#x51CF;&#x5C11;&#x5BC6;&#x5207;&#x76F8;&#x5173;&#x3002;&#x63D0;&#x8BAE;&#x8BBE;&#x7ACB;&#x4E00;&#x4E2A;&#x673A;&#x5236;&#xFF0C;&#x6211;&#x4EEC;&#x8BC1;&#x660E;&#xFF0C;&#x5355;&#x94FE; RNA &#x7684;&#x827E;&#x6ECB;&#x75C5;&#x6BD2;-1 &#x8FDB;&#x884C;&#x7F16;&#x7801;&#x591A;&#x4E2A;&#x5C3F;&#x82F7;&#x5BCC; Toll &#x6837;&#x53D7;&#x4F53; 7/8 (TLR7/8) &#x8BF1;&#x53D1;&#x5F3A;&#x70C8;&#x4F9D;&#x8D56;&#x4E8E; MyD88 &#x7684;&#x6D46;&#x7EC6;&#x80DE;&#x6837;&#x6811;&#x7A81;&#x72B6;&#x7EC6;&#x80DE;&#x548C;&#x5355;&#x6838;&#x7EC6;&#x80DE;&#x6D3B;&#x5316;&#x4EE5;&#x53CA;&#x914D;&#x4EF6;&#x7EC6;&#x80DE;&#x4F9D;&#x8D56; T &#x7EC6;&#x80DE;&#x6D3B;&#x5316;&#x7684;&#x914D;&#x4F53;&#x3002;&#x827E;&#x6ECB;&#x75C5;&#x6BD2;-1 &#x7F16;&#x7801; TLR &#x914D;&#x4F53;&#x53EF;&#x80FD;&#xFF0C;&#x56E0;&#x6B64;&#xFF0C;&#x76F4;&#x63A5;&#x89C2;&#x5BDF;&#x671F;&#x95F4; viremic hiv-1 &#x611F;&#x67D3;&#x7684;&#x514D;&#x75AB;&#x6FC0;&#x6D3B;&#x4F5C;&#x51FA;&#x8D21;&#x732E;&#x3002;&#x8FD9;&#x4E9B;&#x6570;&#x636E;&#x4E3A;&#x6291;&#x5236;&#x5355;&#x53CD;&#x901A;&#x8DEF;&#x76F4;&#x63A5;&#x51CF;&#x5C11;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x548C;&#x76F8;&#x5173;&#x7684;&#x514D;&#x75AB;&#x53D1;&#x75C5;&#x673A;&#x5236;&#x6240;&#x81F4;&#x7684;&#x6162;&#x6027;&#x514D;&#x75AB;&#x6D3B;&#x5316;&#x63D0;&#x4F9B;&#x521D;&#x6B65;&#x7684;&#x7406;&#x7531;&#x3002;

MyD88 &#x4F9D;&#x8D56;&#x4EBA;&#x7C7B;&#x514D;&#x75AB;&#x7F3A;&#x9677;&#x75C5;&#x6BD2;&#x7C7B;&#x578B; 1 &#x7F16;&#x7801; Toll &#x6837;&#x53D7;&#x4F53;&#x914D;&#x4F53;&#x4ECB;&#x5BFC;&#x7684;&#x514D;&#x75AB;&#x6FC0;&#x6D3B;&#x3002;

Immune activation is a major characteristic of human immunodeficiency virus type 1 (HIV-1) infection and a strong prognostic factor for HIV-1 disease progression. The underlying mechanisms leading to immune activation in viremic HIV-1 infection, however, are not fully understood. Here we show that, following the initiation of highly active antiretroviral therapy, the immediate decline of immune activation is closely associated with the reduction of HIV-1 viremia, which suggests a direct contribution of HIV-1 itself to immune activation. To propose a mechanism, we demonstrate that the single-stranded RNA of HIV-1 encodes multiple uridine-rich Toll-like receptor 7/8 (TLR7/8) ligands that induce strong MyD88-dependent plasmacytoid dendritic cell and monocyte activation, as well as accessory cell-dependent T-cell activation. HIV-1-encoded TLR ligands may, therefore, directly contribute to the immune activation observed during viremic HIV-1 infection. These data provide an initial rationale for inhibiting the TLR pathway to directly reduce the chronic immune activation induced by HIV-1 and the associated immune pathogenesis.

MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands.

Activation immunitaire est une caract&eacute;ristique importante du virus de l&#39;immunod&eacute;ficience humaine de type 1 (VIH-1) infection et un puissant facteur pronostique de progression de la maladie (VIH-1. Les m&eacute;canismes sous-jacents, conduisant &agrave; l&#39;activation immunitaire vir&eacute;miques HIV-1 infection, cependant, ne sont pas totalement comprises. Ici, nous montrons que, suivant le d&eacute;but de la th&eacute;rapie antir&eacute;trovirale hautement active, la diminution imm&eacute;diate de l&#39;activation immunitaire est &eacute;troitement li&eacute; &agrave; la r&eacute;duction de la vir&eacute;mie du VIH-1, ce qui sugg&egrave;re une contribution directe du VIH-1 lui-m&ecirc;me &agrave; l&#39;activation immunitaire. Pour proposer un m&eacute;canisme, nous d&eacute;montrons que l&#39;ARN monocat&eacute;naire of HIV-1 encode multiples riche en uridine Toll-like receptor 7/8 (TLR7/8) des ligands qui induisent de fortes cellules dendritiques plasmacytoides de MyD88-d&eacute;pendante et activation des monocytes, ainsi qu&#39;activation des lymphocytes T accessoire-d&eacute;pendant. Ligands TLR cod&eacute;es du VIH-1 peuvent, par cons&eacute;quent, contribuent directement &agrave; l&#39;activation immunitaire observ&eacute;e durant vir&eacute;mique HIV-1 infection. Ces donn&eacute;es fournissent une justification initiale d&#39;inhibition de la voie TLR pour r&eacute;duire directement l&#39;activation immunitaire chronique induite par le VIH-1 et la pathogen&egrave;se immune associ&eacute;e.

Activation immunitaire MyD88-d&eacute;pendante m&eacute;di&eacute;e par des human immunodeficiency virus type 1-encod&eacute;e Toll-like receptor ligands.

Immun-Aktivierung ist ein Hauptmerkmal des humanen Immundefizienz-Virus Typ 1 (HIV-1) Infektion und eine starke prognostischen Faktor f&uuml;r das Fortschreiten der Krankheit in HIV-1. Die zugrunde liegenden Mechanismen zu immun-Aktivierung im vir&auml;mische HIV-1-Infektion, sind jedoch nicht vollst&auml;ndig verstanden. Hier zeigen wir, dass, nach der Einleitung der hochaktiven antiretroviralen Therapie, die sofortige Abnahme der immun-Aktivierung eng verbunden mit der Reduzierung der HIV-1-Vir&auml;mie, die einen direkten Beitrag von HIV-1 sich auf immun-Aktivierung schl&auml;gt. Um einen Mechanismus vorzuschlagen, zeigen wir, dass die einzelstr&auml;ngige RNA von HIV-1 mehrere Uridin-Reich-Toll-Like-Rezeptor 7/8 (TLR7/8) codiert Liganden, die starke MyD88-abh&auml;ngige Plasmacytoid dendritischen Zellen sowie Monozyte Aktivierung und Zubeh&ouml;r-Zelle-abh&auml;ngige T-Zell-Aktivierung veranlassen. HIV-1-codierte TLR-Liganden k&ouml;nnen daher direkt auf die immun-Aktivierung w&auml;hrend vir&auml;mische HIV-1-Infektion beobachtet beitragen. Diese Daten liefern eine erste Begr&uuml;ndung f&uuml;r die Hemmung des TLR-Weges um direkt die chronische immune-Aktivierung induziert durch HIV-1 und der damit verbundenen immun-Pathogenese zu reduzieren.

MyD88-abh&auml;ngige immun-Aktivierung von humanen Immundefizienz-Virus Typ 1-codierte Toll-Like-Rezeptor Liganden vermittelt.

Attivazione immunitaria &egrave; una caratteristica importante del virus dell&#39;immunodeficienza umana di tipo 1 (HIV-1) infezione e un forte fattore prognostico per la progressione della malattia di HIV-1. I meccanismi sottostanti che portano all&#39;attivazione immunitaria nell&#39;infezione da HIV-1 viremici, tuttavia, non sono completamente chiari. Qui vi mostriamo che, dopo l&#39;avvio della terapia antiretrovirale altamente attiva, il declino immediato dell&#39;attivazione immunitaria &egrave; strettamente associato con la riduzione della viremia HIV-1, che suggerisce un contributo diretto di HIV-1, stesso di attivazione immunitaria. Per proporre un meccanismo, dimostriamo che il single-stranded RNA del HIV-1 codifica pi&ugrave; ricchi di uridina recettore Toll-like (TLR7/8) 7/8 ligandi che inducono la cellula dendritica plasmacytoid di forte MyD88-dipendente e attivazione di monociti, cos&igrave; come attivazione delle cellule T-accessorio cellulare-dipendente. Codificato con HIV-1 ligandi TLR possono, pertanto, contribuiscono direttamente all&#39;attivazione immunitaria osservata durante l&#39;infezione da HIV-1 viremici. Questi dati forniscono una motivazione iniziale per inibire il pathway TLR per ridurre direttamente l&#39;attivazione immunitaria cronica indotta da HIV-1 e la patogenesi immunitaria associata.

MyD88-dipendente attivazione immunitaria mediata da ligandi di virus dell&#39;immunodeficienza umana tipo 1-codificato recettore Toll-like.

&#x514D;&#x75AB;&#x6D3B;&#x6027;&#x5316;&#x3067;&#x3042;&#x308B;&#x3072;&#x3068;&#x514D;&#x75AB;&#x4E0D;&#x5168;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x306E;&#x4E3B;&#x8981;&#x306A;&#x7279;&#x5FB4; 1 &#xFF08;HIV-1&#xFF09; &#x611F;&#x67D3;&#x75C7;&#x3068; HIV-1 &#x306E;&#x75C5;&#x6C17;&#x306E;&#x9032;&#x884C;&#x306E;&#x5F37;&#x529B;&#x306A;&#x4E88;&#x6E2C;&#x56E0;&#x5B50;&#x3092;&#x5165;&#x529B;&#x3057;&#x307E;&#x3059;&#x3002;&#x6F5C;&#x4F0F;&#x306E; HIV-1 &#x611F;&#x67D3;&#x3067;&#x514D;&#x75AB;&#x6D3B;&#x6027;&#x5316;&#x306B;&#x3064;&#x306A;&#x304C;&#x308B;&#x6839;&#x672C;&#x7684;&#x306A;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x306F;&#x3001;&#x305F;&#x3060;&#x3057;&#x3001;&#x5B8C;&#x5168;&#x306B;&#x7406;&#x89E3;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x305B;&#x3093;&#x3002;&#x3053;&#x3053;&#x3067;&#x9AD8;&#x6D3B;&#x6027;&#x6297;&#x30EC;&#x30C8;&#x30ED; &#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x7642;&#x6CD5;&#x3001;&#x514D;&#x75AB;&#x6D3B;&#x6027;&#x5316;&#x306E;&#x5373;&#x6642;&#x306E;&#x8870;&#x9000;&#x306E;&#x958B;&#x59CB;&#x3001;&#x6B21;&#x304C; HIV-1 &#x81EA;&#x4F53;&#x514D;&#x75AB;&#x6D3B;&#x6027;&#x5316;&#x3059;&#x308B;&#x306E;&#x306B;&#x76F4;&#x63A5;&#x8CA2;&#x732E;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B; HIV-1 &#x306E;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x8840;&#x75C7;&#x306E;&#x4F4E;&#x6E1B;&#x3068;&#x5BC6;&#x63A5;&#x306B;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;&#x6A5F;&#x69CB;&#x3092;&#x63D0;&#x6848;&#x3059;&#x308B;&#x306E;&#x306B;&#x306F;&#x3001;&#x6211;&#x3005; &#x306F;&#x4E00;&#x672C;&#x9396; RNA &#x306E; HIV-1 &#x8907;&#x6570;&#x30A6;&#x30EA;&#x30B8;&#x30F3; &#x30EA;&#x30C3;&#x30C1; Toll &#x69D8;&#x53D7;&#x5BB9;&#x4F53; 7/8 (TLR7/8) &#x3092;&#x30A8;&#x30F3;&#x30B3;&#x30FC;&#x30C9;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3059;&#x5F37;&#x3044; MyD88 &#x306B;&#x4F9D;&#x5B58;&#x3057;&#x305F;&#x5F62;&#x8CEA;&#x7D30;&#x80DE;&#x69D8;&#x6A39;&#x72B6;&#x7D30;&#x80DE;&#x3068;&#x5358;&#x7403;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3068;&#x30A2;&#x30AF;&#x30BB;&#x30B5;&#x30EA;&#x30FC;&#x7D30;&#x80DE;&#x4F9D;&#x5B58;&#x6027; T &#x7D30;&#x80DE;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3092;&#x8A98;&#x5C0E;&#x3059;&#x308B;&#x914D;&#x4F4D;&#x5B50;&#x3002;HIV 1 &#x30A8;&#x30F3;&#x30B3;&#x30FC;&#x30C9; TLR &#x30EA;&#x30AC;&#x30F3;&#x30C9;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;&#x76F4;&#x63A5;&#x89B3;&#x5BDF;&#x4E2D;&#x306E;&#x6F5C;&#x4F0F;&#x306E; HIV-1 &#x611F;&#x67D3;&#x514D;&#x75AB;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x306B;&#x8CA2;&#x732E;&#x3059;&#x308B;&#x304B;&#x3082;&#x3057;&#x308C;&#x306A;&#x3044;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x30C7;&#x30FC;&#x30BF;&#x306F;&#x3001;&#x76F4;&#x63A5; HIV 1 &#x3068;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x514D;&#x75AB;&#x75C5;&#x614B;&#x306B;&#x3088;&#x3063;&#x3066;&#x8A98;&#x5C0E;&#x3055;&#x308C;&#x308B;&#x6162;&#x6027;&#x306E;&#x514D;&#x75AB;&#x6D3B;&#x6027;&#x5316;&#x3092;&#x6E1B;&#x3089;&#x3059;&#x305F;&#x3081;&#x306B; TLR &#x7D4C;&#x8DEF;&#x3092;&#x963B;&#x5BB3;&#x3059;&#x308B;&#x305F;&#x3081;&#x521D;&#x671F;&#x306E;&#x7406;&#x8AD6;&#x7684;&#x6839;&#x62E0;&#x3092;&#x63D0;&#x4F9B;&#x3057;&#x307E;&#x3059;&#x3002;

&#x3072;&#x3068;&#x514D;&#x75AB;&#x4E0D;&#x5168;&#x30A6;&#x30A4;&#x30EB;&#x30B9; &#x30BF;&#x30A4;&#x30D7; 1 &#x30A8;&#x30F3;&#x30B3;&#x30FC;&#x30C9; Toll &#x69D8;&#x53D7;&#x5BB9;&#x4F53;&#x30EA;&#x30AC;&#x30F3;&#x30C9;&#x306B;&#x3088;&#x308B;&#x5A92;&#x4ECB; MyD88 &#x306B;&#x4F9D;&#x5B58;&#x3059;&#x308B;&#x514D;&#x75AB;&#x6D3B;&#x6027;&#x5316;&#x3002;

&#xBA74;&#xC5ED; &#xD65C;&#xC131;&#xD654;&#xB294; &#xC778;&#xAC04; &#xBA74;&#xC5ED; &#xACB0;&#xD54D; &#xBC14;&#xC774;&#xB7EC;&#xC2A4;&#xC758; &#xC8FC;&#xC694; &#xD2B9;&#xC9D5; 1 (hiv-1) &#xAC10;&#xC5FC; &#xBC0F; &#xC5D0;&#xC774;&#xC988;-1 &#xC9C8;&#xBCD1;&#xC758; &#xC9C4;&#xD589;&#xC5D0; &#xB300; &#xD55C; &#xAC15;&#xD55C; &#xC804;&#xC870; &#xC694;&#xC18C;&#xB97C; &#xC785;&#xB825; &#xD569;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098; viremic &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC;&#xC5D0; &#xBA74;&#xC5ED; &#xD65C;&#xC131;&#xD654;&#xB97C; &#xC120;&#xB3C4; &#xD558;&#xB294; &#xADFC;&#xBCF8;&#xC801;&#xC778; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;, &#xC644;&#xBCBD; &#xD558; &#xAC8C; &#xC774;&#xD574; &#xB418;&#xC9C0; &#xC54A;&#xB294;&#xB2E4;. &#xC5EC;&#xAE30; &#xC6B0;&#xB9AC;&#xAC00;, &#xC5D0;&#xC774;&#xC988;-1&#xC758; &#xC790;&#xCCB4; &#xBA74;&#xC5ED; &#xD65C;&#xC131;&#xD654;&#xC5D0; &#xC9C1;&#xC811;&#xC801;&#xC778; &#xAE30;&#xC5EC;&#xB97C; &#xC81C;&#xC548; &#xC5D0;&#xC774;&#xC988;-1 &#xB2C8;&#xC758; &#xAC10;&#xC18C;&#xC640; &#xBC00;&#xC811; &#xD558; &#xAC8C; &#xAD00;&#xB828; &#xB418;&#xC5B4; &#xACE0;&#xB3C4;&#xB85C; &#xD65C;&#xC131; &#xD56D; &#xB808;&#xD2B8;&#xB85C; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xCE58;&#xB8CC;, &#xBA74;&#xC5ED; &#xD65C;&#xC131;&#xD654;&#xC758; &#xC989;&#xAC01;&#xC801;&#xC778; &#xAC70;&#xBD80;&#xC758; &#xAC1C;&#xC2DC;&#xC5D0; &#xB530;&#xB77C; &#xBCF4;&#xC5EC;&#xC90D;&#xB2C8;&#xB2E4;. &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xC81C;&#xC548; &#xD558;&#xB294; &#xB2E8;&#xC77C; &#xAC00;&#xB2E5; RNA &#xC5D0;&#xC774;&#xC988;-1&#xC758; &#xC778;&#xCF54;&#xB529; &#xC5EC;&#xB7EC; uridine &#xD48D;&#xBD80;&#xD55C; &#xC218;&#xC2E0;&#xC790; &#xAC19;&#xC740; &#xC218;&#xC6A9; &#xCCB4; (TLR7/8) 7/8 &#xC2DC;&#xC5F0; ligands &#xAC15;&#xD55C; MyD88 &#xC885;&#xC18D; plasmacytoid &#xC218;&#xC9C0;&#xC0C1; &#xC138;&#xD3EC; monocyte &#xD65C;&#xC131;&#xD654; &#xBFD0;&#xB9CC; &#xC544;&#xB2C8;&#xB77C; &#xC561;&#xC138;&#xC11C;&#xB9AC; &#xC140; &#xC885;&#xC18D; T &#xC138;&#xD3EC; &#xD65C;&#xC131;&#xD654;&#xB97C; &#xC720;&#xB3C4; &#xD569;&#xB2C8;&#xB2E4;. &#xB530;&#xB77C;&#xC11C; HIV 1 &#xC778;&#xCF54;&#xB529; TLR ligands &#xAD00;&#xCC30; viremic &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC; &#xC2DC; &#xBA74;&#xC5ED; &#xD65C;&#xC131;&#xD654;&#xC5D0; &#xC9C1;&#xC811; &#xAE30;&#xC5EC;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xB370;&#xC774;&#xD130;&#xB294; &#xC9C1;&#xC811; V-1&#xACFC; &#xAD00;&#xB828; &#xB41C; &#xBA74;&#xC5ED; &#xBCD1; &#xC778;&#xC5D0; &#xC758;&#xD574; &#xC720;&#xB3C4; &#xB41C; &#xB9CC;&#xC131; &#xBA74;&#xC5ED; &#xD65C;&#xC131;&#xD654;&#xB97C; &#xC904;&#xC774;&#xAE30; &#xC704;&#xD574; TLR &#xD1B5;&#xB85C; &#xC5B5;&#xC81C; &#xD558;&#xB294; &#xAC83;&#xC5D0; &#xB300; &#xD55C; &#xCD08;&#xAE30; &#xADFC;&#xAC70;&#xB97C; &#xC81C;&#xACF5; &#xD569;&#xB2C8;&#xB2E4;.

MyD88 &#xC885;&#xC18D; &#xBA74;&#xC5ED; &#xD65C;&#xC131;&#xD654; &#xC778;&#xAC04; &#xBA74;&#xC5ED; &#xACB0;&#xD54D; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xC720;&#xD615; &#xC218;&#xC2E0;&#xC790; &#xAC19;&#xC740; &#xC218;&#xC6A9; &#xCCB4; 1&#xB85C; &#xC778;&#xCF54;&#xB529;&#xB41C; ligands &#xC911;&#xC7AC;.

Toll-like receptors (TLRs) mediate inflammation in sepsis, but their role in sepsis-induced respiratory failure is unknown. Hypoxic pulmonary vasoconstriction (HPV) is a unique vasoconstrictor response that diverts blood flow away from poorly ventilated lung regions. HPV is impaired in sepsis and after challenge with the TLR4 agonist lipopolysaccharide (LPS). Unlike TLR4 agonists, which are present only in Gram-negative bacteria, TLR2 agonists are ubiquitously expressed in all of the major classes of microorganisms that cause sepsis, including both Gram-positive and Gram-negative bacteria and fungi. We tested the hypothesis that (S)-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser(S)-Lys(4)-OH, trihydrochloride (Pam3Cys), a TLR2 agonist, impairs HPV and compared selected pulmonary and systemic effects of Pam3Cys vs. LPS. HPV was assessed 22 h after challenge with saline, Pam3Cys, or LPS by measuring the increase in the pulmonary vascular resistance of the left lung before and during left lung alveolar hypoxia produced by left mainstem bronchus occlusion (LMBO). Additional endpoints included arterial blood gases during LMBO, hemodynamic parameters, weight loss, temperature, physical appearance, and several markers of lung inflammation. Compared with saline, challenge with Pam3Cys caused profound impairment of HPV, reduced systemic arterial oxygenation during LMBO, weight loss, leukopenia, and lung inflammation. In addition to these effects, LPS-challenged mice had lower rectal temperatures, metabolic acidosis, and were more ill appearing than Pam3Cys-challenged mice. These data indicate that TLR2 activation impairs HPV and induces deleterious systemic effects in mice and suggest that TLR2 pathways may be important in sepsis-induced respiratory failure.

Activation of Toll-like receptor 2 impairs hypoxic pulmonary vasoconstriction in mice.

PD L1 &#x8868;&#x8FBE;&#x589E;&#x52A0;&#xFF0C;&#x636E;&#x62A5;&#x5728;&#x611F;&#x67D3;&#x827E;&#x6ECB;&#x75C5;&#x6BD2;&#x7684; 1 &#x4E2A;&#x4EBA;&#xFF0C;&#x4F46;&#x901A;&#x5F80; PD L1 &#x4E0A;&#x8C03;&#x673A;&#x5236;&#x6709;&#x5F85;&#x9610;&#x660E;&#x3002;&#x6211;&#x4EEC;&#x5728;&#x8FD9;&#x91CC;&#x5C55;&#x793A;&#xFF0C;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x6D3E;&#x751F; Toll &#x6837;&#x53D7;&#x4F53; (&#x5355;&#x53CD;) 7/8 &#x914D;&#x4F53;&#x53EF;&#x4EE5;&#x8BF1;&#x4F7F; PD L1 &#x6D46;&#x7EC6;&#x80DE;&#x6837;&#x6811;&#x7A81;&#x72B6;&#x7EC6;&#x80DE;&#x3001; myeloidic &#x6811;&#x7A81;&#x72B6;&#x7EC6;&#x80DE;&#x548C;&#x5355;&#x6838;&#x7EC6;&#x80DE;&#x8868;&#x8FBE;&#x4F9D;&#x8D56; MyD88 &#x7684;&#x4E0A;&#x8C03;&#x3002;&#x8FD9;&#x4E9B;&#x6570;&#x636E;&#x8868;&#x660E;&#x4E00;&#x4E2A;&#x673A;&#x5236;&#xFF0C;&#x901A;&#x8FC7;&#x5B83;&#x6D3E;&#x751F;&#x7684;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 TLR &#x914D;&#x4F53;&#x53EF;&#x80FD;&#x6709;&#x52A9;&#x4E8E;&#x529F;&#x80FD;&#x969C;&#x788D;&#x7684;&#x75C5;&#x6BD2;&#x7279;&#x5F02;&#x6027; PD-1 &#x6297;&#x4F53;&#x9633;&#x6027; T &#x7EC6;&#x80DE;&#x5BF9;&#x6297;&#x539F;&#x8BF1;&#x5BFC;&#x7684; PD L1 &#x4E0A;&#x8C03;&#x7684;&#x5355;&#x5143;&#x683C;&#x3002;

&#x4E0A;&#x8C03;&#x7684; PD-L1 &#x5BF9;&#x5355;&#x6838;&#x7EC6;&#x80DE;&#x548C;&#x6811;&#x7A81;&#x72B6;&#x7EC6;&#x80DE;&#x7531;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x6D3E;&#x751F; TLR &#x914D;&#x4F53;&#x3002;

Increased PD-L1 expression has been reported in HIV-1-infected individuals, but the mechanisms leading to PD-L1 upregulation remain to be elucidated. Here we demonstrate that HIV-1-derived Toll-like receptor (TLR)7/8 ligands can induce MyD88-dependent upregulation of PD-L1 on plasmacytoid dendritic cells, myeloidic dendritic cells and monocytes. These data suggest a mechanism through which HIV-1-derived TLR ligands might contribute to the functional impairment of virus-specific PD-1-positive T cells by inducing the upregulation of PD-L1 on antigen-presenting cells.

Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands.

Expression accrue de PD-L1 a &eacute;t&eacute; signal&eacute;e chez les sujets infect&eacute;s par le VIH-1, mais les m&eacute;canismes conduisant &agrave; PD-L1 upregulation restent &agrave; &eacute;lucider. Nous d&eacute;montrons que d&eacute;riv&eacute;s du VIH-1 Toll-like receptor (TLR) 7/8 des ligands peuvent induire upregulation MyD88 d&eacute;pendant de PD-L1 sur les cellules dendritiques plasmacytoides, les myeloidic des cellules dendritiques et les monocytes. Ces donn&eacute;es sugg&egrave;rent un m&eacute;canisme par lequel ligands d&eacute;riv&eacute;s du VIH-1 TLR pourraient contribuer &agrave; l&#39;atteinte fonctionnelle des cellules de T de PD-1 positifs sp&eacute;cifiques du virus en induisant l&#39;upregulation of PD-L1 sur pr&eacute;sentatrices d&#39;antig&egrave;ne des cellules.

Upregulation de PD-L1 sur les monocytes et les cellules dendritiques de VIH-1 provenant de ligands TLR.

Erh&ouml;hte Expression von PD-L1 wurde bei HIV-1-infizierten Personen beschrieben, aber die Mechanismen zur PD-L1 Hochregulation m&uuml;ssen noch gekl&auml;rt werden. Hier zeigen wir, dass HIV-1-abgeleitete Toll-Like-Rezeptor (TLR) 7/8 Liganden MyD88-abh&auml;ngige Hochregulation der PD-L1 Plasmacytoid dendritische Zellen, Myeloidic dendritische Zellen und Monozyten induzieren k&ouml;nnen. Diese Daten legen nahe, einen Mechanismus, durch den HIV-1-abgeleitete TLR-Liganden m&ouml;glicherweise zur Funktionsbeeintr&auml;chtigung von Virus-spezifische PD-1-positiven T-Zellen tr&auml;gt durch induzieren die Hochregulation der PD-L1 auf Antigen-pr&auml;sentierenden, Zellen.

Hochregulation der PD-L1 auf Monozyten und dendritischen Zellen durch HIV-1 abgeleitet TLR-Liganden.

Aumentata espressione di PD-L1 &egrave; stato segnalato in individui HIV-1-infected, ma i meccanismi che portano al PD-L1 upregulation rimangono per essere chiarita. Qui dimostriamo che derivato da HIV-1 Toll-like receptor (TLR) 7/8 ligandi possono indurre MyD88-dipendente sovraregolazione di PD-L1 su plasmacytoid cellule dendritiche, cellule dendritiche myeloidic e monociti. Questi dati suggeriscono un meccanismo attraverso il quale ligandi TLR derivato da HIV-1 potrebbero contribuire alla compromissione funzionale delle cellule T PD-1-positivi specifici per il virus inducendo la sovraregolazione di PD-L1 su presentanti l&#39;antigene delle cellule.

Upregulation di PD-L1 su monociti e cellule dendritiche da HIV-1 derivato ligandi TLR.

HIV-1 &#x611F;&#x67D3;&#x500B;&#x4F53;&#x3067;&#x306F;&#x3001;PD L1 &#x306E;&#x767A;&#x73FE;&#x306E;&#x5897;&#x52A0;&#x304C;&#x5831;&#x544A;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x304C;&#x3001;PD L1 &#x30A2;&#x30C3;&#x30D7;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x306B;&#x3064;&#x306A;&#x304C;&#x308B;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x306F;&#x672A;&#x89E3;&#x660E;&#x306A;&#x90E8;&#x5206;&#x304C;&#x6B8B;&#x308B;&#x3002;&#x3053;&#x3053;&#x3067;&#x6211;&#x3005; &#x304C; HIV 1 &#x7531;&#x6765; Toll &#x69D8;&#x53D7;&#x5BB9;&#x4F53; &#xFF08;TLR&#xFF09; 7/8 &#x3092;&#x793A;&#x3059;&#x914D;&#x4F4D;&#x5B50; MyD88 &#x4F9D;&#x5B58;&#x578B;&#x30A2;&#x30C3;&#x30D7;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3; PD - l1 &#x5F62;&#x8CEA;&#x7D30;&#x80DE;&#x69D8;&#x6A39;&#x72B6;&#x7D30;&#x80DE;&#x3001;myeloidic &#x6A39;&#x72B6;&#x7D30;&#x80DE;&#x3068;&#x5358;&#x7403;&#x3092;&#x8A98;&#x5C0E;&#x3067;&#x304D;&#x308B;&#x3053;&#x3068;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x30C7;&#x30FC;&#x30BF;&#x3092;&#x901A;&#x3058;&#x3066; HIV 1 &#x6D3E;&#x751F; TLR &#x30EA;&#x30AC;&#x30F3;&#x30C9;&#x304B;&#x3082;&#x3057;&#x308C;&#x306A;&#x3044;&#x8CA2;&#x732E;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x7279;&#x7570; PD 1 &#x967D;&#x6027; T &#x7D30;&#x80DE;&#x306E;&#x6A5F;&#x80FD;&#x969C;&#x5BB3;&#x306B;&#x6297;&#x539F;&#x63D0;&#x793A; PD L1 &#x306E;&#x30A2;&#x30C3;&#x30D7;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x3092;&#x8A98;&#x5C0E;&#x3059;&#x308B;&#x3053;&#x3068;&#x306B;&#x3088;&#x3063;&#x3066;&#x6A5F;&#x69CB;&#x3092;&#x63D0;&#x6848;&#x3059;&#x308B;&#x30BB;&#x30EB;&#x3002;

PD &#x30A2;&#x30C3;&#x30D7;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;-&#x5358;&#x7403;&#x3068;&#x6A39;&#x72B6;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x308B; HIV 1 L1 TLR &#x30EA;&#x30AC;&#x30F3;&#x30C9;&#x6D3E;&#x751F;&#x3002;

&#xC99D;&#xAC00; PD L1 &#xC2DD; &#xAC1C;&#xC778; &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC;&#xC5D0; &#xBCF4;&#xACE0; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4; &#xD558;&#xC9C0;&#xB9CC; PD L1 upregulation &#xC774;&#xC5B4;&#xC9C0;&#xB294; &#xBA54;&#xCEE4;&#xB2C8;&#xC998; &#xD574;&#xBA85; &#xB420; &#xB0A8;&#xC544; &#xC788;&#xB2E4;. &#xC5EC;&#xAE30; &#xC218;&#xC6A9; &#xADF8; HIV 1 &#xD30C;&#xC0DD; &#xC218;&#xC2E0;&#xC790; &#xAC19;&#xC740; &#xCCB4; (TLR) 7/8 &#xC2DC;&#xC5F0; ligands plasmacytoid &#xC218;&#xC9C0;&#xC0C1; &#xC138;&#xD3EC;, &#xC218;&#xC9C0;&#xC0C1; &#xC138;&#xD3EC; myeloidic monocytes&#xC5D0; PD-l1&#xC758; upregulation MyD88 &#xC885;&#xC18D;&#xC744; &#xC77C;&#xC73C;&#xD0AC; &#xC218; &#xC788;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xB370;&#xC774;&#xD130;&#xB294; HIV 1 &#xD30C;&#xC0DD; TLR ligands&#xB294; &#xD56D; &#xC6D0; &#xC81C;&#xC2DC;&#xC5D0; PD l1&#xC758; upregulation &#xC720;&#xB3C4; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xAD00;&#xB828; PD 1 &#xC591;&#xC131; T &#xC138;&#xD3EC;&#xC758; &#xAE30;&#xB2A5; &#xC7A5;&#xC560;&#xC5D0; &#xAE30;&#xC5EC;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xC81C;&#xC548; &#xC140;.

Upregulation PD-L1 monocytes &#xBC0F; h i V-1&#xC5D0; &#xC758;&#xD574; &#xC218;&#xC9C0;&#xC0C1; &#xC138;&#xD3EC;&#xC5D0; TLR ligands &#xD30C;&#xC0DD;.

La expresi&oacute;n creciente de PD-L1 se ha divulgado en individuos con infecci&oacute;n por VIH-1, pero los mecanismos que conducen a PD-L1 upregulation siendo ser aclarado. Aqu&iacute; demostramos que derivados de VIH-1 Toll-like receptor (TLR) 7/8 ligandos pueden inducir upregulation MyD88 dependiente de PD-L1 en c&eacute;lulas dendr&iacute;ticas plasmocitoides, myeloidic las c&eacute;lulas dendr&iacute;ticas y los monocitos. Estos datos sugieren un mecanismo a trav&eacute;s del cual ligandos TLR derivados de VIH-1 podr&iacute;an contribuir a la debilitaci&oacute;n funcional de virus espec&iacute;ficos de c&eacute;lulas T de PD-1-positive induciendo la regulaci&oacute;n al alza de PD-L1 en presentadoras de ant&iacute;geno de las c&eacute;lulas.

Upregulation de PD-L1 en monocitos y c&eacute;lulas dendr&iacute;ticas por VIH-1 derivados de ligandos TLR.

TLR2 activation induces cellular and organ inflammation and affects lung function. Because deranged endothelial function and coagulation pathways contribute to sepsis-induced organ failure, we studied the effects of bacterial lipoprotein TLR2 agonists, including peptidoglycan-associated lipoprotein, Pam3Cys, and murein lipoprotein, on endothelial function and coagulation pathways in vitro and in vivo. TLR2 agonist treatment induced diverse human endothelial cells to produce IL-6 and IL-8 and to express E-selectin on their surface, including HUVEC, human lung microvascular endothelial cells, and human coronary artery endothelial cells. Treatment of HUVEC with TLR2 agonists caused increased monolayer permeability and had multiple coagulation effects, including increased production of plasminogen activator inhibitor-1 (PAI-1) and tissue factor, as well as decreased production of tissue plasminogen activator and tissue factor pathway inhibitor. TLR2 agonist treatment also increased HUVEC expression of TLR2 itself. Peptidoglycan-associated lipoprotein induced IL-6 production by endothelial cells from wild-type mice but not from TLR2 knockout mice, indicating TLR2 specificity. Mice were challenged with TLR2 agonists, and lungs and plasmas were assessed for markers of leukocyte trafficking and coagulopathy. Wild-type mice, but not TLR2 mice, that were challenged i.v. with TLR2 agonists had increased lung levels of myeloperoxidase and mRNAs for E-selectin, P-selectin, and MCP-1, and they had increased plasma PAI-1 and E-selectin levels. Intratracheally administered TLR2 agonist caused increased lung fibrin levels. These studies show that TLR2 activation by bacterial lipoproteins broadly affects endothelial function and coagulation pathways, suggesting that TLR2 activation contributes in multiple ways to endothelial activation, coagulopathy, and vascular leakage in sepsis.

Bacterial lipoprotein TLR2 agonists broadly modulate endothelial function and coagulation pathways in vitro and in vivo.

During extended storage, erythrocytes undergo functional changes. These changes reduce the viability of erythrocytes leading to release of oxyhemoglobin, a potent scavenger of nitric oxide. We hypothesized that transfusion of ovine packed erythrocytes (PRBC) stored for prolonged periods would induce pulmonary vasoconstriction in lambs, and that reduced vascular nitric oxide concentrations would increase this vasoconstrictor effect.

Pulmonary hypertension in lambs transfused with stored blood is prevented by breathing nitric oxide.

Mashed potatoes and maize: are the starches safe?

Reduction of pyruvate dehydrogenase (PDH) activity in the brain is associated with neurological deficits in animals resuscitated from cardiac arrest. Thiamine is an essential co-factor of PDH. The objective of this study was to examine whether administration of thiamine improves outcomes after cardiac arrest in mice. Secondarily, we aimed to characterize the impact of cardiac arrest on PDH activity in mice and humans.

Article	Year
Bacterial peptidoglycan-associated lipoprotein: a naturally occurring toll-like receptor 2 agonist that is shed into serum and has synergy with lipopolysaccharide. The Journal of infectious diseases\| PubMed ID: 15717270	2005
MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 17202381	2007
Passive immunization to outer membrane proteins MLP and PAL does not protect mice from sepsis. Molecular medicine (Cambridge, Mass.)\| PubMed ID: 17225874	2006
Toll-like receptor 2 activation by bacterial peptidoglycan-associated lipoprotein activates cardiomyocyte inflammation and contractile dysfunction. Critical care medicine\| PubMed ID: 17255871	2007
MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. Journal of virology\| PubMed ID: 17507480	2007
Activation of Toll-like receptor 2 impairs hypoxic pulmonary vasoconstriction in mice. American journal of physiology. Lung cellular and molecular physiology\| PubMed ID: 18055842	2008
Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands. AIDS (London, England)\| PubMed ID: 18317010	2008
Bacterial lipoprotein TLR2 agonists broadly modulate endothelial function and coagulation pathways in vitro and in vivo. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 21169547	2011
Pulmonary hypertension in lambs transfused with stored blood is prevented by breathing nitric oxide. Anesthesiology\| PubMed ID: 22293717	2012
Mashed potatoes and maize: are the starches safe? Anesthesiology\| PubMed ID: 23340348	2013
Thiamine as a neuroprotective agent after cardiac arrest. Resuscitation\| PubMed ID: 27185216	2016

Aranya Bagchi

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