TLR7-dependent and FcγR-independent production of type I interferon in experimental mouse lupus

Lee, Pui Y.; Kumagai, Yutaro; Li, Yang; Takeuchi, Osamu; Yoshida, Hideo; Weinstein, Jason S.; Kellner, Erinn S.; Nacionales, Dina C.; Barker, Tolga; Kelly-Scumpia, Kindra M.; Rooijen, Nico van; Kumar, Himanshu; Kawai, Taro; Satoh, Minoru; Akira, Shizuo; Reeves, Westley H.

doi:10.1084/jem.20080462

Cited by 205 publications

(256 citation statements)

References 67 publications

Supporting

Mentioning

230

Contrasting

Unclassified

Order By: Relevance

“…7,35,36 Therefore, we injected AC into WT and CD300f-deficient mice, in the presence of pristane, an alkane that induces a SLE-like disease by promoting the release of auto-antigens from AC. 37,38 Although pristane alone did not cause any difference in splenomegaly between Cd300f +/+ and Cd300f CD300f deficiency causes an accelerated autoimmune response in Fcgr2b −/− mice. The spontaneous development of autoimmunity in Fcgr2b −/− C57BL/6 mice is due to the decreased activation threshold of B cells, which are easily activated by self-antigen-autoantibody immunocomplexes.…”

Section: Resultsmentioning

confidence: 90%

Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

Tian

Lee

et al. 2016

Cell Death Differ

View full text Add to dashboard Cite

Homeostasis requires the immunologically silent clearance of apoptotic cells before they become pro-inflammatory necrotic cells. CD300f (CLM-1) is a phosphatidylserine receptor known to positively regulate efferocytosis by macrophages, and CD300f genedeficient mice are predisposed to develop a lupus-like disease. Here we show that, in contrast to CD300f function in macrophages, its expression inhibits efferocytosis by DC, and its deficiency leads to enhanced antigen processing and T-cell priming by these DC. The consequences are the expansion of memory T cells and increased ANA levels in aged CD300f-deficient mice, which predispose CD300f-deficient mice to develop an overt autoimmune disease when exposed to an overload of apoptotic cells, or an exacerbated autoimmunity when combined with FcγRIIB deficiency. Thus, our data demonstrates that CD300f helps to maintain immune homeostasis by promoting macrophage clearance of self-antigens, while conversely inhibiting DC uptake and presentation of self-antigens.

show abstract

Section: Resultsmentioning

confidence: 90%

Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

Tian

Lee

et al. 2016

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…injection of the hydrocarbon oil TMPD (also known as "pristane"). These features include a type I IFN signature, ANAs, and glomerulonephritis (24,25). Importantly, TMPD-induced autoimmunity is dependent upon TLR7 and type I IFNs (26).…”

Section: Sting Deficiency Results In the Increased Expression Of Ifn-mentioning

confidence: 99%

“…Importantly, TMPD-induced autoimmunity is dependent upon TLR7 and type I IFNs (26). Pristane injection of C57/Bl6 mice results in an early and persistent peritoneal inflammation and the recruitment of TLR7 hi Ly6C hi monocytes, a potential source of type I IFNs, in this model (25). We thus sought to determine if TMPD-induced, TLR-dependent inflammation is also modulated by STING.…”

Section: Sting Deficiency Results In the Increased Expression Of Ifn-mentioning

confidence: 99%

Suppression of systemic autoimmunity by the innate immune adaptor STING

Sharma

Campbell

Chan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

148

139

View full text Add to dashboard Cite

Cytosolic DNA-sensing pathways that signal via Stimulator of interferon genes (STING) mediate immunity to pathogens and also promote autoimmune pathology in DNaseII- and DNaseIII-deficient mice. In contrast, we report here that STING potently suppresses inflammation in a model of systemic lupus erythematosus (SLE). Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING-deficient autoimmune-prone mice compared with STING-sufficient littermates. As a result, STING-deficient autoimmune-prone mice had significantly shorter lifespans than controls. Importantly, Toll-like receptor (TLR)-dependent systemic inflammation during 2,6,10,14-tetramethylpentadecane (TMPD)-mediated peritonitis was similarly aggravated in STING-deficient mice. Mechanistically, STING-deficient macrophages failed to express negative regulators of immune activation and thus were hyperresponsive to TLR ligands, producing abnormally high levels of proinflammatory cytokines. This hyperreactivity corresponds to dramatically elevated numbers of inflammatory macrophages and granulocytes in vivo. Collectively these findings reveal an unexpected negative regulatory role for STING, having important implications for STING-directed therapies.

show abstract

“…Thus, TLR7 tolerance may restrain B cell innate immune responses and prevent immunopathology associated with uncontrolled proinflammatory cytokine production. However, in an autoimmune setting, type I IFN produced by DCs in response to autoantigen-containing immune complexes may prevent or reverse tolerance induction, and promote autoimmunity (18,23). Conversely, tolerance induction upon repeated administration of TLR ligands may contribute to the limitation of success obtained by systemic use of TLR7 ligands as antitumor agents (52).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, both TLR7 and TLR9 agonists are strong inducers of type I IFN production (20), and IFN-stimulated gene expression in the peripheral blood cells of SLE patients correlates with autoantibodies and disease severity (21). TLR7 is also implicated in the pathogenesis of SLE in several mouse models (22,23). However, the molecular mechanisms involved in the interactions between TLR7 and IFNAR signals are not understood.…”

mentioning

confidence: 99%

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Poovassery

Bishop

2012

The Journal of Immunology

View full text Add to dashboard Cite

Toll-like receptor 7 (TLR7) signals to B cells are critically involved in the innate immune response to microbes, as well as pathogenesis of autoimmune diseases, but the molecular mechanisms that normally regulate these responses are incompletely understood. We previously reported that repeated stimulation through TLR7 induces a state of hyporesponsiveness (TLR tolerance) in both human and mouse B cells, characterized by marked inhibition of particular signaling pathways. BCR signals prevent and overcome TLR7 tolerance. Because optimal responses to TLR7 in B cells require type I IFN, we investigated whether BCR-mediated effects on TLR7 tolerance are mediated by type I IFN receptor (IFNAR) signals. Surprisingly, although BCR-mediated reversal of TLR7 tolerance was IFNAR independent, IFNAR signals alone also blocked TLR7 tolerance, despite enhancing TLR7 expression. Both BCR and IFNAR signals restored the phosphorylation of the transcriptional regulator c-Jun, but only BCR signals blocked the tolerance-mediated inhibition of JNK. Both BCR and IFNAR-mediated regulation was dependent on activation of the PI3K/Akt/mammalian target of rapamycin signaling pathway, indicating a central role for this axis in integrating TLR7, BCR, and IFNAR signals in B cells. These new findings reveal distinct and overlapping signaling mechanisms used by BCR and IFNAR in the regulation of TLR7 tolerance and activation.

show abstract

TLR7-dependent and FcγR-independent production of type I interferon in experimental mouse lupus

Cited by 205 publications

References 67 publications

Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

Suppression of systemic autoimmunity by the innate immune adaptor STING

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Contact Info

Product

Resources

About