IL-10 Regulates Murine Lupus

Yin, Zhinan; Bahtiyar, Gül; Zhang, Na; Liu, Lanzhen; Zhu, Ping; Robert, Marie E.; McNiff, Jennifer M.; Madaio, Michael P.; Craft, Joe

doi:10.4049/jimmunol.169.4.2148

Cited by 210 publications

(188 citation statements)

References 41 publications

(48 reference statements)

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“…5), which could be responsible for skin disease exacerbation in CD1d KO mice. In fact, a recent study described significant acceleration of skin disease in IL-10 KO MRL-lpr mice [37]. IL-10 also plays a critical role in the development of immune tolerance [38].…”

Section: Discussionmentioning

confidence: 99%

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

et al. 2004

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Mechanisms responsible for the development of autoimmune skin disease in humans and animal models with lupus remain poorly understood. In this study, we have investigated the role of CD1d, an antigen-presenting molecule known to activate natural killer T cells, in the development of inflammatory dermatitis in lupus-susceptible MRL-lpr/lpr mice. In particular, we have established MRL-lpr/lpr mice carrying a germ-line deletion of the CD1d genes. We demonstrate that CD1d-deficient MRL-lpr/lpr mice, as compared with wild-type littermates, have more frequent and more severe skin disease, with increased local infiltration with mast cells, lymphocytes and dendritic cells, including Langerhans cells. CD1d-deficient MRL-lpr/ lpr mice had increased prevalence of CD4 + T cells in the spleen and liver and of TCR § g + B220 + cells in lymph nodes. Furthermore, CD1d deficiency was associated with decreased T cell production of type 2 cytokines and increased or unchanged type 1 cytokines. These findings indicate a regulatory role of CD1d in inflammatory dermatitis. Understanding the mechanisms by which CD1d deficiency results in splenic T cell expansion and cytokine alterations, with increased dermal infiltration of dendritic cells and lymphocytes in MRL-lpr/lpr mice, will have implications for the pathogenesis of inflammatory skin diseases.

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Section: Discussionmentioning

confidence: 99%

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

et al. 2004

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“…In our studies, we have shown that dual engagement of SR-B1 and TLR9 by CpG negatively regulates the production of pro-inflammatory mediators such as IL-6 and IL-10. Although the role of these cytokines in promoting autoimmune disease is complex and not fully resolved, IL-6 and IL-10 are biomarkers of systemic lupus erythematosis (44) and have been implicated in its pathogenesis (45)(46)(47)(48)(49). IL-6 regulates B cell differentiation and Ig production, but this action seems more critical to isotype switching and not IgM production (50).…”

Section: Discussionmentioning

confidence: 99%

Mechanism and Regulatory Function of CpG Signaling via Scavenger Receptor B1 in Primary B Cells

Zhu¹,

Liu²,

Treml

et al. 2009

Journal of Biological Chemistry

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It is well established that CpG promotes pro-inflammatory cytokine and antibody production by B cells via the Toll-like receptor 9 (TLR9)-dependent pathway. However, scavenger receptors (SRs) are also capable of binding such pathogen-derived molecules, yet their contribution to CpG-induced signaling events has not yet been evaluated. Here we identified a novel TLR9-independent mechanism of CpG-induced signaling and immune function that is mediated by the scavenger B1 receptor (SR-B1). Specifically, we show that CpG/SR-B1 triggers calcium entry into primary B lymphocytes via phospholipase C␥-1-mediated activation of TRPC3 channels and also B cell adhesion to vascular cell adhesion molecule-1. CpG-induced calcium signals and vascular cell adhesion molecule-1 adhesion are TLR9-independent and are mediated exclusively by SR-B1. Although proinflammatory cytokine and Ig production induced by CpG require TLR9 expression, we also found that SR-B1 negatively regulates TLR9-dependent production of interleukin-6, interleukin-10, and IgM. Thus, our results provide a novel perspective on the complexity of CpG signaling within B cells by demonstrating that SR-B1 is an alternative pathway for nucleic acid-induced signaling that provides feedback inhibition on specific TLR9-dependent responses of B cells. Consequently, these results have wide implications for understanding the mechanisms regulating immune tolerance to nucleic acids and pathogen-associated molecules.Stimulus-induced dynamic changes in the concentration of cytoplasmic calcium are primary determinants of the activation, immunological function, and developmental fate of lymphocytes. Calcium signaling through the B cell antigen receptor (BCR) 2 complex is initiated by the activation of proximal tyrosine kinases Lyn and Syk, which phosphorylate the adaptor BLNK to facilitate its association with and activation of PLC␥-2. PLC␥2 hydrolyzes phosphatidylinositol 4,5-bisphosphate into diacylglycerol and 1,4,5-inositol trisphosphate (IP 3 ) (for review see Ref. 1), which activates IP 3 receptor/channels that mediate Ca 2ϩ release from endoplasmic reticulum into the cytosol (2) (for review see Refs. 3, 4). Ca 2ϩ release from endoplasmic reticulum stores and the resulting depletion of Ca 2ϩ(not an increase in cytoplasmic [Ca 2ϩ ]) are the central and prerequisite events required to activate plasma membrane "storeoperated" calcium release-activated calcium (CRAC) channels.CRAC channels are responsible for antigen receptor-triggered calcium entry; however, a growing body of evidence suggests that CRAC channels do not underlie all the diverse calcium-regulated responses of lymphocytes, particularly those triggered by innate stimuli. For example, we previously identified several calcium-permeant non-selective cation channels (NSCCs) that are uniquely activated by distinct arachidonic acid-derived (eicosanoid) inflammatory mediators and by mechanical stimuli (5-7). Thus, multiple calcium-permeant channels with distinct activation mechanisms may underlie stimulus-specific calciu...

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“…Indeed, CpG-ODN have been demonstrated to induce IL-10 in lupus B cells, particularly those with the marginal zone B cell phenotype (41,42) and then to down-regulate proinflammatory cytokines (42). IL-10-producing B cells are known to regulate autoimmunity (43) and IL-10-deficient MRL-Fas lpr mice developed severe lupus (44). Interestingly, these mice present an exacerbated disease phenotype with early appearance of skin lesions, more severe renal disease and augmented production of IgG2a antidsDNA autoantibodies, a phenotype resembling that observed in our TLR9-deficient lupus mice.…”

Section: Figurementioning

confidence: 99%

Role of TLR9 in Anti-Nucleosome and Anti-DNA Antibody Production in lpr Mutation-Induced Murine Lupus

Lartigue

Courville

Auquit

et al. 2006

The Journal of Immunology

144

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Systemic lupus erythematosus is characterized by the production of autoantibodies directed against nuclear Ags, including nucleosome and DNA. TLR9 is thought to play a role in the production of these autoantibodies through the capacity of nuclear immunogenic particles to interact both with BCR and TLR9. To determine the role of TLR9 in SLE, C57BL/6-lpr/lpr-TLR9−/− and TLR9+/+ mice were analyzed. The abrogation of TLR9 totally impaired the production of anti-nucleosome Abs, whereas no difference was observed in the frequency of anti-dsDNA autoantibodies whose titer was strikingly higher in TLR9−/− mice. In addition a higher rate of mesangial proliferation was observed in the kidney of TLR9-deficient animals. These results indicate that in C57BL/6-lpr/lpr mice, TLR9 is absolutely required for the anti-nucleosome Ab response but not for anti-dsDNA Ab production which is involved in mesangial proliferation.

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IL-10 Regulates Murine Lupus

Cited by 210 publications

References 41 publications

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

Mechanism and Regulatory Function of CpG Signaling via Scavenger Receptor B1 in Primary B Cells

Role of TLR9 in Anti-Nucleosome and Anti-DNA Antibody Production in lpr Mutation-Induced Murine Lupus

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