Suppression of systemic autoimmunity by the innate immune adaptor STING

Sharma, Shrutie; Campbell, Allison M.; Chan, Jennie; Schattgen, Stefan A.; Orlowski, Gregory M.; Nayar, Ribhu; Huyler, Annie; Nündel, Kerstin; Mohan, Chandra; Berg, Leslie J.; Shlomchik, Mark J.; Marshak‐Rothstein, Ann; Fitzgerald, Katherine A.

doi:10.1073/pnas.1420217112

Cited by 148 publications

(157 citation statements)

References 48 publications

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“…However, in STING-deficient lupus mice, lymphoid hypertrophy, autoantibody production, serum cytokine levels are increased markedly, compared to their STING-sufficient littermates [91]. STING-deficient macrophages fail to express negative regulators of TLR signalling, including cytoplasmic zinc finger protein A20 and suppressor of cytokine signalling1 (SOCS1) and 3 (SOCS3), which leads to hyper-responsiveness to TLR ligands and abnormal production of proinflammatory cytokines [91]. Collectively, these findings reveal that STING has both positive and negative regulatory roles in immune responses.…”

Section: Sting-dependent Pathwaymentioning

confidence: 96%

“…Depletion of cGAS, STING, IRF3 or IFN-I receptor in TREX1-deficient mice rescues these mice from autoimmune disorders and mortality [87,89,90], suggesting that the cGAS-STING-IRF3 axis-mediated IFN-I production is responsible for the development of autoimmune disorders in these TREX1-deficient mice. However, in STING-deficient lupus mice, lymphoid hypertrophy, autoantibody production, serum cytokine levels are increased markedly, compared to their STING-sufficient littermates [91]. STING-deficient macrophages fail to express negative regulators of TLR signalling, including cytoplasmic zinc finger protein A20 and suppressor of cytokine signalling1 (SOCS1) and 3 (SOCS3), which leads to hyper-responsiveness to TLR ligands and abnormal production of proinflammatory cytokines [91].…”

Section: Sting-dependent Pathwaymentioning

confidence: 99%

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Self-dsDNA in the pathogenesis of systemic lupus erythematosus

Bai

Tong

Liu

et al. 2017

Clinical and Experimental Immunology

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SummarySystemic lupus erythematosus (SLE) is a systemic and poly-aetiological autoimmune disease characterized by the production of antibodies to autologous double-stranded DNA (dsDNA) which serve as diagnostic and prognostic markers. The defective clearance of apoptotic material, together with neutrophil extracellular traps (NETs), provides abundant chromatin or self-dsDNA to trigger the production of anti-dsDNA antibodies, although the mechanisms remain to be elucidated. In SLE patients, the immune complex (IC) of dsDNA and its autoantibodies trigger the robust type I interferon (IFN-I) production through intracellular DNA sensors, which drives the adaptive immune system to break down self-tolerance. In this review, we will discuss the potential resources of self-dsDNA, the mechanisms of self-dsDNA-mediated inflammation through various DNA sensors and its functions in SLE pathogenesis.

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Section: Sting-dependent Pathwaymentioning

confidence: 96%

Section: Sting-dependent Pathwaymentioning

confidence: 99%

Self-dsDNA in the pathogenesis of systemic lupus erythematosus

Bai

Tong

Liu

et al. 2017

Clinical and Experimental Immunology

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“…Inactivation of the cGAS/STING pathway in murine lupus models is often associated with changes in anti-dsDNA Ab production and lymphoid hypertrophy (67)(68)(69), while iRhom2 deficiency did not affect anti-dsDNA Ab production in Fcgr2b -/-mice. Moreover, we found no change in the type I IFN signature in iRhom2-deficient Fcgr2b -/-mice.…”

Section: Rhbdf2mentioning

confidence: 97%

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

Qing¹,

Chinenov²,

Redecha³

et al. 2018

Journal of Clinical Investigation

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“…Likewise, we have reported that apoptotic cells drive rapid expression of the tryptophan (Trp)-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in MARCO + marginal zone (MZ) MΦs that is critical for prevention of apoptotic cell-driven autoimmunity (6). Moreover, studies by our group (6) and Sharma et al (9) have shown a link between a loss of IDO1 activity and exaggeration of autoimmune pathology in MRL lpr/lpr mice.…”

mentioning

confidence: 93%

“…On a molecular level, the mechanisms driving the initial tolerogenic response of myeloid cells to apoptotic material in vivo are poorly defined, although studies suggest a direct role for inhibitory signaling via the MAPK pathway (8), and a recent report indicated that responses to cytoplasmic DNA may be a key mechanism of tolerance to self (9). Likewise, we have reported that apoptotic cells drive rapid expression of the tryptophan (Trp)-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in MARCO + marginal zone (MZ) MΦs that is critical for prevention of apoptotic cell-driven autoimmunity (6).…”

mentioning

confidence: 99%

The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity

Ravishankar

Liu

Shinde

et al. 2015

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

128

127

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Efficient apoptotic cell clearance and induction of immunologic tolerance is a critical mechanism preventing autoimmunity and associated pathology. Our laboratory has reported that apoptotic cells induce tolerance by a mechanism dependent on the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in splenic macrophages (MΦ). The metabolic-stress sensing protein kinase GCN2 is a primary downstream effector of IDO1; thus, we tested its role in apoptotic cell-driven immune suppression. In vitro, expression of IDO1 in MΦs significantly enhanced apoptotic celldriven IL-10 and suppressed IL-12 production in a GCN2-dependent mechanism. Suppression of IL-12 protein production was due to attenuation of IL-12 mRNA association with polyribosomes inhibiting translation while IL-10 mRNA association with polyribosomes was not affected. In vivo, apoptotic cell challenge drove a rapid, GCN2-dependent stress response in splenic MΦs with increased IL-10 and TGF-β production, whereas myeloid-specific deletion of GCN2 abrogated regulatory cytokine production with provocation of inflammatory T-cell responses to apoptotic cell antigens and failure of long-tolerance induction. Consistent with a role in prevention of apoptotic cell driven autoreactivity, myeloid deletion of GCN2 in lupus-prone mice resulted in increased immune cell activation, humoral autoimmunity, renal pathology, and mortality. In contrast, activation of GCN2 with an agonist significantly reduced anti-DNA autoantibodies and protected mice from disease. Thus, this study implicates a key role for GCN2 signals in regulating the tolerogenic response to apoptotic cells and limiting autoimmunity.immunometabolism | stress | tolerance | autoimmunity | apoptosis M ultiple lines of evidence suggest that apoptotic cells are a major source of autoantigens in the autoimmune disease systemic lupus erythematosus (SLE). This evidence includes the fact that the dominant autoantigens targeted in SLE are largely nuclear components that are exposed on apoptotic blebs (1, 2). Moreover, the body of evidence suggests that increased cell death and defective clearance are primary drivers of SLE development and progression (3).In homeostatic conditions, apoptotic cells drive suppressive innate and adaptive tolerogenic immune responses that protect against initiation of inflammatory autoimmunity. Macrophages (MΦ) are key drivers of the early innate response to apoptotic cells (4, 5), and recent work has shown that tissue-resident MΦs are responsible for initial IL-10 production, promoting regulatory adaptive immunity to apoptotic cell antigens and prevention of inflammatory autoimmunity (4, 6, 7).On a molecular level, the mechanisms driving the initial tolerogenic response of myeloid cells to apoptotic material in vivo are poorly defined, although studies suggest a direct role for inhibitory signaling via the MAPK pathway (8), and a recent report indicated that responses to cytoplasmic DNA may be a key mechanism of tolerance to self (9). Likewise, we have reported that apoptoti...

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Suppression of systemic autoimmunity by the innate immune adaptor STING

Cited by 148 publications

References 48 publications

Self-dsDNA in the pathogenesis of systemic lupus erythematosus

Self-dsDNA in the pathogenesis of systemic lupus erythematosus

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity

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