fluorescence-activated-cell-sorting-for-purification-plasmacytoid

Fluorescence-activated Cell Sorting for Purification of Plasmacytoid Dendritic Cells from the Mouse Bone Marrow

Fluorescence-activated cell sorting (FACS) is a technique to purify specific cell populations based on phenotypes detected by flow cytometry. This method ...

analyses-proteinuria-renal-infiltration-leukocytes-renal-deposition

Analyses of Proteinuria, Renal Infiltration of Leukocytes, and Renal Deposition of Proteins in Lupus-prone MRL/lpr Mice

Systemic lupus erythematosus (SLE) is an autoimmune disorder with no known cure and is characterized by persistent inflammation in many organs, including ...

analysis-fecal-microbiota-dynamics-lupus-prone-mice-using-simple-cost

Analysis of Fecal Microbiota Dynamics in Lupus-Prone Mice Using a Simple, Cost-Effective DNA Isolation Method

Gut microbiota has an important role in educating the immune system. This relationship is extremely important for understanding autoimmune diseases that ...

Virginia Polytechnic Institute and State University

MRL/lpr mice have been extensively used as a murine model of lupus. Disease progression in MRL/lpr mice can differ among animal facilities, suggesting a role for environmental factors. We noted a phenotypic drift of our in-house colony, which was the progeny of mice obtained from The Jackson Laboratory (JAX; stocking number 000485), that involved attenuated glomerulonephritis, increased splenomegaly, and reduced lymphadenopathy. To validate our in-house mice as a model of lupus, we compared these mice with those newly obtained from JAX, which were confirmed to be genetically identical to our in-house mice. Surprisingly, the new JAX mice exhibited a similar phenotypic drift, most notably the attenuation of glomerulonephritis. Interestingly, our in-house colony differed from JAX mice in body weight and kidney size (both sexes), as well as in splenic size, germinal center formation, and level of anti-dsDNA auto-IgG in the circulation (male only). In addition, we noted differential expression of microRNA (miR)-21 and miR-183 that might explain the splenic differences in males. Furthermore, the composition of gut microbiota was different between in-house and new JAX mice at early time points, which might explain some of the renal differences (e.g., kidney size). However, we could not identify the reason for attenuated glomerulonephritis, a shared phenotypic drift between the two colonies. It is likely that this was due to certain changes of environmental factors present in both JAX and our facilities. Taken together, these results suggest a significant phenotypic drift in MRL/lpr mice in both colonies that may require strain recovery from cryopreservation.

Phenotypic Drift in Lupus-Prone MRL/lpr Mice: Potential Roles of MicroRNAs and Gut Microbiota.

&#x3053;&#x3053;&#x3067;&#x6211;&#x3005; &#x306F;&#x8EE2;&#x5199;&#x56E0;&#x5B50;&#x767E;&#x79D1;&#x4E8B;&#x5178; &#xFF08;TFe&#xFF09;&#x3001;&#x30AA;&#x30FC;&#x30D7;&#x30F3; &#x30A2;&#x30AF;&#x30BB;&#x30B9;&#x3068;&#x30B3;&#x30E9;&#x30DC;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x306E;&#x539F;&#x5247;&#x306B;&#x8A2D;&#x7ACB;&#x3055;&#x308C;&#x305F;&#x65B0;&#x3057;&#x3044; web &#x30D9;&#x30FC;&#x30B9;&#x5927;&#x8981;&#x30DF;&#x30CB;&#x30EC;&#x30D3;&#x30E5;&#x30FC;&#x8A18;&#x4E8B;&#x8EE2;&#x5199;&#x56E0;&#x5B50; (TFs) &#x306E;&#x5B58;&#x5728;&#x3057;&#x307E;&#x3059;&#x3002;&#x672C;&#x30B3;&#x30F3;&#x30BD;&#x30FC;&#x30B7;&#x30A2;&#x30E0;&#x306E; 100 &#x4EE5;&#x4E0A;&#x306E;&#x7814;&#x7A76;&#x8005;&#x306E;&#x9069;&#x5207;&#x306A;&#x4EBA;&#x9593;&#x3001;&#x30DE;&#x30A6;&#x30B9;&#x4EE5;&#x4E0A; 130 &#x30DF;&#x30CB;&#x30EC;&#x30D3;&#x30E5;&#x30FC;&#x8A18;&#x4E8B;&#x7DCF;&#x79F0;&#x3057;&#x3066;&#x8CA2;&#x732E;&#x3057;&#x3001;&#x30E9;&#x30C3;&#x30C8; TFs&#x3002; &#x6CE8;&#x76EE;&#x3059;&#x3079;&#x304D;&#x6A5F;&#x80FD;&#x3001;TFe &#x306E;&#x30A6;&#x30A7;&#x30D6;&#x30B5;&#x30A4;&#x30C8;&#x306E;&#x9AD8;&#x54C1;&#x8CEA;&#x306E; PDF &#x30B8;&#x30A7;&#x30CD;&#x30EC;&#x30FC;&#x30BF;&#x30FC;&#x3068;&#x30D7;&#x30ED;&#x30B0;&#x30E9;&#x30E0;&#x306B;&#x3088;&#x308B;&#x30C7;&#x30FC;&#x30BF;&#x691C;&#x7D22;&#x306E;&#x305F;&#x3081;&#x306E; web API &#x304C;&#x542B;&#x307E;&#x308C;&#x307E;&#x3059;&#x3002;TFe &#x6025;&#x901F;&#x306B;&#x66F8;&#x304B;&#x308C;&#x3001;&#x5206;&#x91CE;&#x306E;&#x5C02;&#x9580;&#x5BB6;&#x306B;&#x3088;&#x3063;&#x3066;&#x541F;&#x5473;&#x306E;&#x7C21;&#x6F54;&#x306A;&#x8981;&#x7D04;&#x306E;&#x914D;&#x4FE1;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x906D;&#x9047; TFs &#x306B;&#x3064;&#x3044;&#x3066;&#x306E;&#x79D1;&#x5B66;&#x8005;&#x3092;&#x6559;&#x80B2;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x76EE;&#x6307;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;TFe http://www.cisreg.ca/tfe &#x3067;&#x5229;&#x7528;&#x53EF;&#x80FD;&#x3067;&#x3059;&#x3002;

&#x8EE2;&#x5199;&#x56E0;&#x5B50;&#x306E;&#x767E;&#x79D1;&#x4E8B;&#x5178;&#x3002;

&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x63D0;&#x51FA;&#x8F6C;&#x5F55;&#x56E0;&#x5B50;&#x767E;&#x79D1;&#x5168;&#x4E66; (TFe) &#x65B0;&#x57FA;&#x4E8E; web &#x7684;&#x6C47;&#x7F16;&#x7684;&#x8FF7;&#x4F60;&#x8BC4;&#x8BBA;&#x6587;&#x7AE0;&#x7684;&#x8F6C;&#x5F55;&#x56E0;&#x5B50; &#xFF08;TFs&#xFF09;&#xFF0C;&#x5EFA;&#x57FA;&#x4E8E;&#x5F00;&#x653E;&#x548C;&#x534F;&#x4F5C;&#x7684;&#x539F;&#x5219;&#x3002;&#x6211;&#x4EEC;&#x8D22;&#x56E2;&#x7684;&#x8D85;&#x8FC7; 100 &#x7684;&#x7814;&#x7A76;&#x8005;&#x4EEC;&#x96C6;&#x4F53;&#x4F5C;&#x51FA;&#x4E86;&#x8D21;&#x732E;&#x8D85;&#x8FC7; 130 &#x8FF7;&#x4F60;&#x7684;&#x8BC4;&#x8BBA;&#x6587;&#x7AE0;&#xFF0C;&#x5BF9;&#x76F8;&#x5173;&#x7684;&#x4EBA;&#x7C7B;&#xFF0C;&#x9F20;&#x6807;&#x548C; TFe &#x7F51;&#x7AD9;&#x5927;&#x9F20; TFs&#x3002; &#x663E;&#x8457;&#x7279;&#x70B9;&#x5305;&#x62EC;&#x4E00;&#x4E2A;&#x9AD8;&#x8D28;&#x91CF;&#x7684; PDF &#x751F;&#x6210;&#x5668;&#x548C; web API &#x8FDB;&#x884C;&#x7F16;&#x7A0B;&#x7684;&#x6570;&#x636E;&#x68C0;&#x7D22;&#x3002;TFe &#x65E8;&#x5728;&#x8FC5;&#x901F;&#x6559;&#x5BFC;&#x4ED6;&#x4EEC;&#x9047;&#x5230;&#x901A;&#x8FC7;&#x7B80;&#x6D01;&#x6458;&#x8981;&#x7F16;&#x5199;&#x548C;&#x5BA1;&#x6838;&#x7684;&#x9886;&#x57DF;&#x7684;&#x4E13;&#x5BB6;&#x63D0;&#x4F9B;&#x7684; TFs &#x6709;&#x5173;&#x79D1;&#x5B66;&#x5BB6;&#x3002;&#x53EF;&#x5728; http://www.cisreg.ca/tfe TFe&#x3002;

&#x8F6C;&#x5F55;&#x56E0;&#x5B50;&#x767E;&#x79D1;&#x5168;&#x4E66;&#x3002;

Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.

The transcription factor encyclopedia.

Nous pr&eacute;sentons ici l&#39;Encyclop&eacute;die de facteur de Transcription (TFe), un nouveau webmail recueil du mini revue d&#39;articles sur des facteurs de transcription (TFs) qui est fond&eacute; sur les principes de libre acc&egrave;s et la collaboration. Notre consortium de plus de 100 chercheurs a contribu&eacute; collectivement plus de 130 articles de synth&egrave;se mini souris humaine, pertinente et rat TFs. caract&eacute;ristiques notables du site TFe incluent un g&eacute;n&eacute;rateur de PDF de haute qualit&eacute; et web API pour la r&eacute;cup&eacute;ration des donn&eacute;es par programmation. TFe vise &agrave; &eacute;duquer rapidement les scientifiques sur la TFs qu&#39;ils rencontrent en offrant des r&eacute;sum&eacute;s succincts &eacute;crit et contr&ocirc;l&eacute;s par des experts dans le domaine. TFe est disponible &agrave; http://www.cisreg.ca/tfe.

L&#39;Encyclop&eacute;die de facteur de transcription.

Hier pr&auml;sentieren wir die Transkription Faktor Enzyklop&auml;die (TFe), eine neue webbasierte Kompendium der Mini Review-Artikel &uuml;ber Transkriptionsfaktoren (TFs), die auf den Grunds&auml;tzen des open Access und Zusammenarbeit beruht. Unser Konsortium von &uuml;ber 100 Forscher hat kollektiv &uuml;ber 130 Mini Review-Artikel &uuml;ber relevante menschliche, Maus und Ratte TFs. bemerkenswerte Eigenschaften der TFe Website umfassen eine qualitativ hochwertige PDF-Generator und Web-API f&uuml;r das programmgesteuerte Abrufen. TFe soll Wissenschaftler &uuml;ber den TFs rasch zu erziehen, auf die sie sto&szlig;en, durch die Lieferung von knappe Zusammenfassungen geschrieben und von Experten gepr&uuml;ft. TFe ist unter http://www.cisreg.ca/tfe verf&uuml;gbar.

Die Transkription Faktor Enzyklop&auml;die.

Qui vi presentiamo l&#39;enciclopedia di fattore di trascrizione (TFe), un nuovo web-based compendio di articoli mini recensione su fattori di trascrizione (TFs) che &egrave; fondato sui principi dell&#39;accesso aperto e collaborazione. Il nostro Consorzio di oltre 100 ricercatori ha contribuito collettivamente oltre 130 articoli mini recensione su pertinente e umano, del mouse e ratto TFs. caratteristiche notevoli del sito TFe includono un generatore di PDF di alta qualit&agrave; e web API per il recupero dei dati a livello di codice. TFe mira a educare rapidamente gli scienziati circa il TFs incontrano attraverso la consegna di succinte riassunti scritti e controllati da esperti del settore. TFe &egrave; disponibile presso http://www.cisreg.ca/tfe.

L&#39;enciclopedia del fattore di trascrizione.

&#xC5EC;&#xAE30;&#xC5D0; &#xC6B0;&#xB9AC;&#xAC00; &#xD604;&#xC7AC; &#xB179;&#xC74C; &#xBC29;&#xC1A1; &#xC694;&#xC778; &#xBC31;&#xACFC; &#xC0AC;&#xC804; (TFe), &#xC81C; &#xC0C8;&#xB85C;&#xC6B4; &#xC6F9; &#xAE30;&#xBC18; &#xC694; &#xBBF8;&#xB2C8; &#xAC80;&#xD1A0; &#xAE30;&#xC0AC; &#xB179;&#xC74C; &#xBC29;&#xC1A1; &#xC694;&#xC778; (TFs)&#xC758; &#xC624;&#xD508; &#xC561;&#xC138;&#xC2A4;&#xC640; &#xD611;&#xB825;&#xC758; &#xC6D0;&#xCE59;&#xC5D0; &#xAE30;&#xCD08; &#xD558;&#xB294;. 100 &#xAC1C; &#xC774;&#xC0C1;&#xC758; &#xC5F0;&#xAD6C; &#xC790;&#xB4E4;&#xC740; &#xC6B0;&#xB9AC;&#xC758; &#xCEE8;&#xC18C;&#xC2DC;&#xC5C4; 130 &#xBBF8;&#xB2C8; &#xAC80;&#xD1A0; &#xAE30;&#xC0AC; &#xAD00;&#xB828; &#xC778;&#xAC04;, &#xB9C8;&#xC6B0;&#xC2A4;&#xC5D0; &#xAE30;&#xC5EC;&#xD55C; &#xCD1D;&#xCE6D; &#xBC0F; &#xC950; TFs. &#xC8FC;&#xBAA9;&#xD560; &#xB9CC;&#xD55C; &#xAE30;&#xB2A5;&#xC740; TFe &#xC6F9;&#xC0AC;&#xC774;&#xD2B8;&#xC758; &#xB192;&#xC740; &#xD488;&#xC9C8; PDF &#xC0DD;&#xC131;&#xAE30; &#xBC0F; &#xD504;&#xB85C;&#xADF8;&#xB798;&#xBC0D; &#xBC29;&#xC2DD;&#xC73C;&#xB85C; &#xB370;&#xC774;&#xD130; &#xAC80;&#xC0C9;&#xC744; &#xC704;&#xD55C; &#xC6F9; API &#xD3EC;&#xD568;. TFe &#xBE60;&#xB974;&#xAC8C; &#xC791;&#xC131; &#xD558; &#xACE0; &#xBD84;&#xC57C;&#xC758; &#xC804;&#xBB38;&#xAC00; &#xC758;&#xD574; &#xD640;&#xB354; &#xAC04;&#xACB0; &#xC694;&#xC57D;&#xC758; &#xB0A9;&#xD488;&#xC744; &#xD1B5;&#xD574; &#xBC1C;&#xC0DD; &#xD558;&#xB294; Tfs&#xC5D0; &#xB300; &#xD55C; &#xACFC;&#xD559;&#xC790; &#xB4E4;&#xC744; &#xAD50;&#xC721; &#xD558;&#xB294; &#xAC83;&#xC744; &#xBAA9;&#xD45C;&#xB85C; &#xD569;&#xB2C8;&#xB2E4;. Tfe&#xB294; http://www.cisreg.ca/tfe&#xC5D0;&#xC11C; &#xC0AC;&#xC6A9;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xB179;&#xC74C; &#xBC29;&#xC1A1; &#xC694;&#xC778; &#xBC31;&#xACFC; &#xC0AC;&#xC804;&#xC785;&#xB2C8;&#xB2E4;.

Aqu&iacute; presentamos la transcripci&oacute;n Factor enciclopedia (TFe), un compendio de art&iacute;culos de mini revisi&oacute;n sobre factores de transcripci&oacute;n (TFs) nuevo a basadas en web que se basa en los principios del acceso abierto y la colaboraci&oacute;n. Nuestro Consorcio de m&aacute;s de 100 investigadores colectivamente ha contribuido con m&aacute;s de 130 art&iacute;culos de mini revisi&oacute;n pertinente humano, rat&oacute;n y rata TFs. de la P&aacute;gina Web de TFe destaca un generador PDF de alta calidad y web API para recuperaci&oacute;n de datos mediante programaci&oacute;n. TFe pretende educar r&aacute;pidamente a los cient&iacute;ficos sobre el TFs se encuentran a trav&eacute;s de la entrega de res&uacute;menes sucintos escrito y validada por expertos en la materia. TFe est&aacute; disponible en http://www.cisreg.ca/tfe.

La enciclopedia del factor de transcripci&oacute;n.

Using mice that lack recombination activating gene-2 (Rag2), we have found that bone marrow-derived plasmacytoid dendritic cells (pDCs) as main producers of interferon-α (IFNα) require Rag2 for normal development. This is a novel function for Rag2, whose classical role is to initiate B and T cell development. Here we showed that a population of common progenitor cells in the mouse bone marrow possessed the potential to become either B cells or pDCs upon appropriate stimulations, and the lack of Rag2 hindered the development of both types of progeny cells. A closer look at pDCs revealed that Rag2⁻/⁻ pDCs expressed a high level of Ly6C and were defective at producing IFNα in response to CpG, a ligand for toll-like receptor 9. This phenotype was not shared by Rag1⁻/⁻ pDCs. The induction of CCR7, CD40 and CD86 with CpG, however, was normal in Rag2⁻/⁻ pDCs. In addition, Rag2⁻/⁻ pDCs retained the function to promote antibody class switching and plasma cell formation through producing IL-6. Further analysis showed that interferon regulatory factor-8, a transcription factor important for both IFNα induction and pDC development, was dysregulated in pDCs lacking Rag2. These results indicate that the generation of interferon response in pDCs requires Rag2 and suggest the lymphoid origin of bone marrow-derived pDCs.

Recombination activating gene-2 regulates CpG-mediated interferon-α production in mouse bone marrow-derived plasmacytoid dendritic cells.

Gut microbiota has been recognized as an important environmental factor in health, as well as in metabolic and immunological diseases, in which perturbation of the host gut microbiota is often observed in the diseased state. However, little is known on the role of gut microbiota in systemic lupus erythematosus. We investigated the effects of host genetics, sex, age, and dietary intervention on the gut microbiome in a murine lupus model. In young, female lupus-prone mice resembling women at childbearing age, a population with the highest risk for lupus, we found marked depletion of lactobacilli, and increases in Lachnospiraceae and overall diversity compared to age-matched healthy controls. The predicted metagenomic profile in lupus-prone mice showed a significant enrichment of bacterial motility- and sporulation-related pathways. Retinoic acid as a dietary intervention restored lactobacilli that were downregulated in lupus-prone mice, and this correlated with improved symptoms. The predicted metagenomes also showed that retinoic acid reversed many lupus-associated changes in microbial functions that deviated from the control. In addition, gut microbiota of lupus-prone mice were different between sexes, and an overrepresentation of Lachnospiraceae in females was associated with an earlier onset of and/or more severe lupus symptoms. Clostridiaceae and Lachnospiraceae, both harboring butyrate-producing genera, were more abundant in the gut of lupus-prone mice at specific time points during lupus progression. Together, our results demonstrate the dynamics of gut microbiota in murine lupus and provide evidence to suggest the use of probiotic lactobacilli and retinoic acid as dietary supplements to relieve inflammatory flares in lupus patients.

Dynamics of gut microbiota in autoimmune lupus.

Plasmacytoid dendritic cells (pDCs) are professional type I IFN producers believed to promote lupus. However, questions exist about whether they function at the same level throughout the course of lupus disease. We analyzed high-purity pDCs sorted from lupus mice. Although pDCs produced a large amount of IFN-α during disease initiation, those sorted from late-stage lupus mice were found to be defective in producing IFN-α. These pDCs expressed an increased level of MHC, suggesting a functional drift to Ag presentation. We examined the potential mechanism behind the defect and identified a novel transcriptional factor, Foxj2, which repressed the expression of several genes in pDCs, but not IFN-α. Dysregulation in pDCs appears to be predisposed, because they exhibited an altered transcriptional profile before the onset of clinical signs. Our results suggest that pDCs do not function the same throughout the disease course and lose the ability to produce IFN-α in late-stage lupus mice.

Cutting Edge: Plasmacytoid Dendritic Cells in Late-Stage Lupus Mice Defective in Producing IFN-α.

Prior studies have shown that pan-HDAC inhibition can decrease disease in lupus mice; however, the mechanisms(s) remain to be elucidated. MRL/MpJ-Fas(lpr) (MRL/lpr) mice develop a lupus-like disease characterized by anti-dsDNA production, lymphoproliferation, and immune complex-mediated glomerulonephritis. Early- and late-disease (12 and 20weeks-of-age respectively) female MRL/lpr mice were compared to age-matched, healthy C57BL/6 mice for HDAC expression and activity in bone marrow (BM) B cells, splenic B and T cells, and glomerular cells. We found that HDAC6 was significantly overexpressed in B cells, splenic T cells and glomerular cells, whereas HDAC9 expression was significantly increased in splenic T cells, BM B cells and glomerular cells. Due to the overexpression of HDAC6, we tested whether treatment with a selective HDAC6 inhibitor (ACY-738) or a pan-HDAC inhibitor (TsA) would decrease HDAC activity. ACY-738 significantly reduced cytoplasmic HDAC activity whereas TsA significantly decreased both nuclear and cytoplasmic HDAC activity. In vitro studies in mesangial cells showed that ACY-738 increased α-tubulin and Hsp90 acetylation resulting in decreased nuclear activation of NF-κB. Treatment of pre-B cells with ACY-738 decreased the Bcl-2:Bax ratio leading to a pro-apoptotic environment. These results suggest that increased HDAC6 expression and activity contribute to SLE pathogenesis, and isoform-selective HDAC inhibitors may prove beneficial in the treatment of SLE by acetylating key signaling and transcription factors in inflammation and cell activation.

HDAC expression and activity is upregulated in diseased lupus-prone mice.

We sought to determine if a selective HDAC6 inhibitor (ACY-738) decreases disease in NZB/W mice. From 22 to 38weeks-of-age, mice were injected intraperitoneally with 5 or 20mg/kg of ACY-738, or vehicle control. Body weight and proteinuria were measured every 2weeks, while sera anti-dsDNA, Ig isotypes, and cytokine levels were measured every 4weeks. Kidney disease was determined by evaluation of sera, urine, immune complex deposition, and renal pathology. Flow cytometric analysis assessed thymic, splenic, bone marrow, and peripheral lymphocyte differentiation patterns. Our results showed HDAC6 inhibition decreased SLE disease by inhibiting immune complex-mediated glomerulonephritis, sera anti-dsDNA levels, and inflammatory cytokine production and increasing splenic Treg cells. Inhibition of HDAC6 increased the percentage of cells in the early-stage developmental fractions of both pro- and pre-B cells. These results suggest that specific HDAC6 inhibition may be able to decrease SLE disease by altering aberrant T and B cell differentiation.

Specific HDAC6 inhibition by ACY-738 reduces SLE pathogenesis in NZB/W mice.

Dendritic cells (DC) play an important role in the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease with multiple tissue manifestations. In this review, we summarize recent studies on the roles of conventional DC and plasmacytoid DC in the development of both murine lupus and human SLE. In the past decade, studies using selective DC depletions have demonstrated critical roles of DC in lupus progression. Comprehensive in vitro and in vivo studies suggest activation of DC by self-antigens in lupus pathogenesis, followed by breakdown of immune tolerance to self. Potential treatment strategies targeting DC have been developed. However, many questions remain regarding the mechanisms by which DC modulate lupus pathogenesis that require further investigations.

Breakdown of Immune Tolerance in Systemic Lupus Erythematosus by Dendritic Cells.

Lupus nephritis (LN) is a major cause of morbidity and mortality in the patients with systemic lupus erythematosus (SLE), an autoimmune disease with damage to multiple organs. Leukocyte recruitment into the inflamed kidney is a critical step to promote LN progression, and the chemokine/chemokine receptor system is necessary for leukocyte recruitment. In this review, we summarize recent studies on the roles of chemokines and chemokine receptors in the development of LN and discuss the potential and hurdles of developing novel, chemokine-based drugs to treat LN.

Chemokines and Chemokine Receptors in the Development of Lupus Nephritis.

To date, there are 18 histone deacetylase (HDAC) enzymes, divided into four classes, which alter protein function by removing acetyl groups from lysine residues. Prior studies report that non-selective HDAC inhibitors decrease disease in lupus mouse models. Concern for adverse side effects of non-selective HDAC inhibition supports investigation of selective-HDAC inhibition. We hypothesized that a selective HDAC-6 inhibitor (HDAC6i) will alleviate disease in a mouse model of lupus by increasing acetylation of alpha-tubulin. Intraperitoneal injections of the selective HDAC6i ACY-1083 (0.3 mg/kg, 1 mg/kg, or 3 mg/kg), vehicle control, or dexamethasone were administered to 21-week-old, female NZB/W mice, 5 days a week, for 13 weeks. Disease progression was evaluated by proteinuria, serum levels of anti-dsDNA antibody, cytokines and immunoglobulins, and post mortem evaluation of nephritis and T cell populations in the spleen. HDAC6i treatment decreased proteinuria, glomerular histopathology, IgG, and C3 scores when compared to vehicle-treated mice. Within glomeruli of HDAC6i-treated mice, there was increased acetylation of alpha-tubulin and decreased NF-κB. Additionally, HDAC6i decreased serum IL-12/IL-23 and Th17 cells in the spleen. Taken together, these results suggest HDAC-6 inhibition may decrease lupus nephritis in NZB/W mice via mechanisms involving acetylation of alpha-tubulin and decreased NF-κB in glomeruli as well as inhibition of Th17 cells.

Treatment with a selective histone deacetylase 6 inhibitor decreases lupus nephritis in NZB/W mice.

Systemic lupus erythematosus, characterized by persistent inflammation, is a complex autoimmune disorder with no known cure. Immunosuppressants used in treatment put patients at a higher risk of infections. New knowledge of disease modulators, such as symbiotic bacteria, can enable fine-tuning of parts of the immune system, rather than suppressing it altogether.

Control of lupus nephritis by changes of gut microbiota.

Gut microbiota and the immune system interact to maintain tissue homeostasis, but whether this interaction is involved in the pathogenesis of systemic lupus erythematosus (SLE) is unclear. Here we report that oral antibiotics given during active disease removed harmful bacteria from the gut microbiota and attenuated SLE-like disease in lupus-prone mice. Using MRL/lpr mice, we showed that antibiotics given after disease onset ameliorated systemic autoimmunity and kidney histopathology. They decreased IL-17-producing cells and increased the level of circulating IL-10. In addition, antibiotics removed Lachnospiraceae and increased the relative abundance of Lactobacillus spp., two groups of bacteria previously shown to be associated with deteriorated or improved symptoms in MRL/lpr mice, respectively. Moreover, we showed that the attenuated disease phenotype could be recapitulated with a single antibiotic vancomycin, which reshaped the gut microbiota and changed microbial functional pathways in a time-dependent manner. Furthermore, vancomycin treatment increased the barrier function of the intestinal epithelium, thus preventing the translocation of lipopolysaccharide, a cell wall component of Gram-negative Proteobacteria and known inducer of lupus in mice, into the circulation. These results suggest that mixed antibiotics or a single antibiotic vancomycin ameliorate SLE-like disease in MRL/lpr mice by changing the composition of gut microbiota.

Antibiotics ameliorate lupus-like symptoms in mice.

Gut microbiota dysbiosis has been observed in a number of autoimmune diseases. However, the role of the gut microbiota in systemic lupus erythematosus (SLE), a prototypical autoimmune disease characterized by persistent inflammation in multiple organs of the body, remains elusive. Here we report the dynamics of the gut microbiota in a murine lupus model, NZB/W F1, as well as intestinal dysbiosis in a small group of SLE patients with active disease. The composition of the gut microbiota changed markedly before and after the onset of lupus disease in NZB/W F1 mice, with greater diversity and increased representation of several bacterial species as lupus progressed from the predisease stage to the diseased stage. However, we did not control for age and the cage effect. Using dexamethasone as an intervention to treat SLE-like signs, we also found that a greater abundance of a group of lactobacilli (for which a species assignment could not be made) in the gut microbiota might be correlated with more severe disease in NZB/W F1 mice. Results of the human study suggest that, compared to control subjects without immune-mediated diseases, SLE patients with active lupus disease possessed an altered gut microbiota that differed in several particular bacterial species (within the genera  and  and an unnamed genus in the family ) and was less diverse, with increased representation of Gram-negative bacteria. The / ratios did not differ between the SLE microbiota and the non-SLE microbiota in our human cohort. SLE is a complex autoimmune disease with no known cure. Dysbiosis of the gut microbiota has been reported for both mice and humans with SLE. In this emerging field, however, more studies are required to delineate the roles of the gut microbiota in different lupus-prone mouse models and people with diverse manifestations of SLE. Here, we report changes in the gut microbiota in NZB/W F1 lupus-prone mice and a group of SLE patients with active disease.

Gut Microbiota in Human Systemic Lupus Erythematosus and a Mouse Model of Lupus.

A leaky gut has been observed in a number of autoimmune diseases including type 1 diabetes, multiple sclerosis, inflammatory bowel disease, and systemic lupus erythematosus. Previous studies from our laboratory have shown that lupus mice also bear a leaky gut and that the intestinal barrier function can be enhanced by gut colonization of probiotics such as  spp Retinoic acid (RA) can increase the relative abundance of  spp. in the gut. Interestingly, RA has also been shown to strengthen the barrier function of epithelial cells in vitro and in the absence of probiotic bacteria. These reports bring up an interesting question of whether RA exerts protective effects on the intestinal barrier directly or through regulating the microbiota colonization. In this review, we will discuss the roles of RA in immunomodulation, recent literature on the involvement of a leaky gut in different autoimmune diseases, and how RA shapes the outcomes of these diseases.

Retinoic Acid, Leaky Gut, and Autoimmune Diseases.

Dysbiosis of gut microbiota exists in the pathogenesis of many autoimmune diseases, including systemic lupus erythematosus (lupus). Lupus patients who experienced pregnancy usually had more severe disease flares post-delivery. However, the possible role of gut microbiota in the link between pregnancy and exacerbation of lupus remains to be explored.

Pregnancy and lactation interfere with the response of autoimmunity to modulation of gut microbiota.

We previously showed that all--retinoic acid (tRA), an active metabolite of vitamin A, exacerbated pre-existing autoimmunity in lupus; however, its effects before the development of autoimmunity are unknown. Here, using a pristane-induced model, we show that tRA exerts differential effects when given at the initiation vs. continuation phase of lupus. Unlike tRA treatment during active disease, pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin β1, activating bone marrow conventional dendritic cells (cDCs), and upregulating the interaction of ICAM-1 and LFA-1 in the spleen, indicating an active process of leukocyte activation and trafficking. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated the expression of genes associated with cDC activation and migration. Post-pristane tRA treatment, on the other hand, did not significantly alter the severity of glomerulonephritis; rather, it exerted immunosuppressive functions of decreasing circulatory and renal deposition of autoantibodies as well as suppressing the renal expression of proinflammatory cytokines and chemokines. Together, these findings suggest that tRA differentially modulate lupus-associated kidney inflammation depending on the time of administration. Interestingly, both pre- and post-pristane treatments with tRA reversed pristane-induced leaky gut and modulated the gut microbiota in a similar fashion, suggesting a gut microbiota-independent mechanism by which tRA affects the initiation vs. continuation phase of lupus.

Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus.

The intestine is a particularly dynamic environment in which the host constantly interacts with trillions of symbiotic bacteria called the microbiota. Using quorum sensing (QS) communication, bacteria can coordinate their social behavior and influence host cell activities in a non-invasive manner. Nowadays, a large amount of research has greatly spurred the understanding of how bacterial QS communication regulates bacterial cooperative behaviors due to coexistence and host-microbe interactions. In this review, we discuss bacterial QS in the gut and its role in biofilm formation. As a biological barrier, the mucosal immune system can effectively prevent pathogenic microorganisms and other immunogenic components from entering the internal environment of the host. We focus on the relationship between biofilm and intestinal mucosal immunity, and how probiotic bacteria may regulate them. This review is to provide a theoretical basis for the development of new techniques including probiotics targeting the intestinal barrier function, thereby improving gut health.

Quorum Sensing, Biofilm, and Intestinal Mucosal Barrier: Involvement the Role of Probiotic.

Infants are prone to enteric infections due to an underdeveloped immune system. The maternal microbiota, through shaping the neonatal microbiota, helps establish a strong immune system in infants. We and others have observed the phenomenon of enhanced early neonatal immunoglobulin A (IgA) production in preweaning immunocompetent mice nursed by immunodeficient dams. Here, we show that this enhancement of IgA in neonates results from maternally derived microbiota. In addition, we have found that the neonatal IgA production can be induced by , which is enriched in the milk of immunodeficient dams. Moreover, we show that while the production of neonatal IgA is dependent on neonatal T cells, the immunodeficient maternal microbiota-mediated enhancement of neonatal IgA has a T cell-independent component. Indeed, this enhancement may be dependent on type 3 innate lymphoid cells in the neonatal small intestinal lamina propria. Interestingly, maternal microbiota-induced neonatal IgA does not cross-react with common enteric pathogens. Future investigations will determine the functional consequences of having this extra IgA.

ArticleTotal : 3	Year
Publication title	2016
Publication title	2022
Publication title	2022

Article	Year
Phenotypic Drift in Lupus-Prone MRL/lpr Mice: Potential Roles of MicroRNAs and Gut Microbiota. ImmunoHorizons\| PubMed ID: 35039434	2022
The transcription factor encyclopedia. Genome biology\| PubMed ID: 22458515	2012
Recombination activating gene-2 regulates CpG-mediated interferon-α production in mouse bone marrow-derived plasmacytoid dendritic cells. PloS one\| PubMed ID: 23110142	2012
Dynamics of gut microbiota in autoimmune lupus. Applied and environmental microbiology\| PubMed ID: 25261516	2014
Cutting Edge: Plasmacytoid Dendritic Cells in Late-Stage Lupus Mice Defective in Producing IFN-α. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 26447229	2015
HDAC expression and activity is upregulated in diseased lupus-prone mice. International immunopharmacology\| PubMed ID: 26471208	2015
Specific HDAC6 inhibition by ACY-738 reduces SLE pathogenesis in NZB/W mice. Clinical immunology (Orlando, Fla.)\| PubMed ID: 26604012	2016
Breakdown of Immune Tolerance in Systemic Lupus Erythematosus by Dendritic Cells. Journal of immunology research\| PubMed ID: 27034965	2016
Chemokines and Chemokine Receptors in the Development of Lupus Nephritis. Mediators of inflammation\| PubMed ID: 27403037	2016
Treatment with a selective histone deacetylase 6 inhibitor decreases lupus nephritis in NZB/W mice. Histology and histopathology\| PubMed ID: 28245046	2017
Control of lupus nephritis by changes of gut microbiota. Microbiome\| PubMed ID: 28697806
Antibiotics ameliorate lupus-like symptoms in mice. Scientific reports\| PubMed ID: 29057975	2017
Gut Microbiota in Human Systemic Lupus Erythematosus and a Mouse Model of Lupus. Applied and environmental microbiology\| PubMed ID: 29196292	2018
Retinoic Acid, Leaky Gut, and Autoimmune Diseases. Nutrients\| PubMed ID: 30081517	2018
Pregnancy and lactation interfere with the response of autoimmunity to modulation of gut microbiota. Microbiome\| PubMed ID: 31311609	2019
Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus. Frontiers in immunology\| PubMed ID: 32265909	2020
Quorum Sensing, Biofilm, and Intestinal Mucosal Barrier: Involvement the Role of Probiotic. Frontiers in cellular and infection microbiology\| PubMed ID: 33102249	2020
Regulation of neonatal IgA production by the maternal microbiota. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 33619092	2021

Xin M. Luo

Biography

JoVE Journal Publications

Other Publications