cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE

Motwani, Mona; McGowan, Jason D.; Antonovitch, Jennifer; Gao, Kevin MingJie; Jiang, Zhaozhao; Sharma, Shrutie; Baltus, Gretchen A.; Nickerson, Kevin M.; Marshak‐Rothstein, Ann; Fitzgerald, Katherine A.

doi:10.3389/fimmu.2021.605930

Cited by 34 publications

(17 citation statements)

References 56 publications

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“…Our findings are overall in line with a recent study reporting that the cGAS-STING pathway does not promote autoimmunity in two murine models of SLE, the pristane induced lupus model and the genetically programmed MRL/lpr model ( 49 ). Whereas that study investigated the role of global cGAS or STING knock-out, thus affecting myeloid, lymphoid and stromal cells alike, the present study interrogated the role of the cGAS-STING pathway in GC B cells specifically.…”

Section: Discussionsupporting

confidence: 92%

B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

et al. 2021

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Germinal centers (GCs) are induced microanatomical structures wherein B cells undergo affinity maturation to improve the quality of the antibody response. Although GCs are crucial to appropriate humoral responses to infectious challenges and vaccines, many questions remain about the molecular signals driving B cell participation in GC responses. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an important mediator of type I interferon and proinflammatory cytokine responses during infection and cellular stress. Recent studies have reported important roles for STING in B cell responses, including an impact on GC B cells and downstream antibody responses, which could have great consequences for vaccine design and understanding STING-associated interferonopathies. GCs are also involved in untoward reactions to autoantigens in a plethora of autoimmune disorders, and it is generally thought that these responses coopt the mechanisms used in foreign antigen-directed GCs. Here, we set out to investigate the importance of the cGAS-STING pathway in autoreactive B cell responses. In a direct competition scenario in a murine mixed bone marrow chimera model of autoreactive GCs, we find that B cell intrinsic deficiency of cGAS, STING, or the type I interferon receptor IFNAR, does not impair GC participation, whereas Toll-like receptor (TLR)-7 deficiency mediates a near-complete block. Our findings suggest that physiological B cell responses are strictly sustained by signals linked to BCR-mediated endocytosis. This wiring of B cell signals may enable appropriate antibody responses, while at the same time restricting aberrant antibody responses during infections and in autoimmune or autoinflammatory settings.

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Section: Discussionsupporting

confidence: 92%

B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

et al. 2021

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“…Recent work has suggested that STING simultaneously stimulates the production of pro-and anti-inflammatory cytokines to facilitate the maintenance of gut homeostasis (Ahn et al, 2017), and studies in mouse models of systemic lupus erythematosus (SLE) have indicated STING signaling can be pro-or anti-inflammatory depending on the model (Sharma et al, 2015;Thim-uam et al, 2020;Motwani et al, 2021). Still, the autoimmune syndrome SAVI, caused by gain-offunction mutations in STING, results in excessive inflammation, indicating a primarily pro-inflammatory role for STING (Liu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Type I Interferon Response Is Mediated by NLRX1-cGAS-STING Signaling in Brain Injury

Fritsch

Basso

et al. 2022

Front. Mol. Neurosci.

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BackgroundInflammation is a significant contributor to neuronal death and dysfunction following traumatic brain injury (TBI). Recent evidence suggests that interferons may be a key regulator of this response. Our studies evaluated the role of the Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes (cGAS-STING) signaling pathway in a murine model of TBI.MethodsMale, 8-week old wildtype, STING knockout (−/−), cGAS−/−, and NLRX1−/− mice were subjected to controlled cortical impact (CCI) or sham injury. Histopathological evaluation of tissue damage was assessed using non-biased stereology, which was complemented by analysis at the mRNA and protein level using qPCR and western blot analysis, respectively.ResultsWe found that STING and Type I interferon-stimulated genes were upregulated after CCI injury in a bi-phasic manner and that loss of cGAS or STING conferred neuroprotection concomitant with a blunted inflammatory response at 24 h post-injury. cGAS−/− animals showed reduced motor deficits 4 days after injury (dpi), and amelioration of tissue damage was seen in both groups of mice up to 14 dpi. Given that cGAS requires a cytosolic damage- or pathogen-associated molecular pattern (DAMP/PAMP) to prompt downstream STING signaling, we further demonstrate that mitochondrial DNA is present in the cytosol after TBI as one possible trigger for this pathway. Recent reports suggest that the immune modulator NLR containing X1 (NLRX1) may sequester STING during viral infection. Our findings show that NLRX1 may be an additional regulator that functions upstream to regulate the cGAS-STING pathway in the brain.ConclusionsThese findings suggest that the canonical cGAS-STING-mediated Type I interferon signaling axis is a critical component of neural tissue damage following TBI and that mtDNA may be a possible trigger in this response.

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“…Initial studies in lupus mouse models indicated that STING suppresses systemic autoimmunity, including kidney disease 120 . Accordingly, loss of Cgas on the lupus-prone MRL/Fas.lpr background resulted in increased proteinuria and cellular infiltration in the kidney 121 . By contrast, a pro-inflammatory effect of STING activation was reported to drive lupus pathology in FcgR2b −/− mice 96 , 122 .…”

Section: Cgas–sting In Diseasementioning

confidence: 98%

Role of the cGAS–STING pathway in systemic and organ-specific diseases

Skopelja-Gardner

Elkon

2022

Nat Rev Nephrol

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Cells are equipped with numerous sensors that recognize nucleic acids, which probably evolved for defence against viruses. Once triggered, these sensors stimulate the production of type I interferons and other cytokines that activate immune cells and promote an antiviral state. The evolutionary conserved enzyme cyclic GMP–AMP synthase (cGAS) is one of the most recently identified DNA sensors. Upon ligand engagement, cGAS dimerizes and synthesizes the dinucleotide second messenger 2′,3′-cyclic GMP–AMP (cGAMP), which binds to the endoplasmic reticulum protein stimulator of interferon genes (STING) with high affinity, thereby unleashing an inflammatory response. cGAS-binding DNA is not restricted by sequence and must only be >45 nucleotides in length; therefore, cGAS can also be stimulated by self genomic or mitochondrial DNA. This broad specificity probably explains why the cGAS–STING pathway has been implicated in a number of autoinflammatory, autoimmune and neurodegenerative diseases; this pathway might also be activated during acute and chronic kidney injury. Therapeutic manipulation of the cGAS–STING pathway, using synthetic cyclic dinucleotides or inhibitors of cGAMP metabolism, promises to enhance immune responses in cancer or viral infections. By contrast, inhibitors of cGAS or STING might be useful in diseases in which this pro-inflammatory pathway is chronically activated.

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cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE

Cited by 34 publications

References 56 publications

B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

Type I Interferon Response Is Mediated by NLRX1-cGAS-STING Signaling in Brain Injury

Role of the cGAS–STING pathway in systemic and organ-specific diseases

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