Hierarchy of clinical manifestations in SAVI N153S and V154M mouse models

Abstract

Studies over the past decade have revealed a central role for innate immune sensors in autoimmune and autoinflammatory diseases. cGAS, a cytosolic DNA sensor, detects both foreign and host DNA and generates a second-messenger cGAMP, which in turn binds and activates stimulator of IFN genes (STING), leading to induction of type I interferons and inflammatory cytokines. Recently, gain-offunction mutations in STING have been identified in patients with STING-associated vasculopathy with onset in infancy (SAVI). SAVI patients present with early-onset systemic inflammation and interstitial lung disease, resulting in pulmonary fibrosis and respiratory failure. Here, we describe two independent SAVI mouse models, harboring the two most common mutations found in patients. A direct comparison of these strains reveals a hierarchy of immune abnormalities, lung inflammation and fibrosis, which do not depend on either IFN-α/β receptor signaling or mixed lineage kinase domainlike pseudokinase (MLKL)-dependent necroptotic cell death pathways. Furthermore, radiation chimera experiments reveal how bone marrow from the V154M mutant mice transfer disease to the WT host, whereas the N153S does not, indicating mutation-specific disease outcomes. Moreover, using radiation chimeras we find that T cell lymphopenia depends on T cell-intrinsic expression of the SAVI mutation. Collectively, these mutant mice recapitulate many of the disease features seen in SAVI patients and highlight mutation-specific functions of STING that shed light on the heterogeneity observed in SAVI patients. STING | SAVI | type I interferonopathies | T cells | cell death N ucleic acids are readily detected by nucleic acid sensors that survey cells for signs of infection or tissue damage. Engagement of a diverse collection of RNA and DNA sensors trigger host-defense responses to curb pathogen replication and initiate beneficial repair responses to tissue injury. The DNA sensor cGAS (cGMP-AMP synthase) is a nucleotidyl transferase that detects double-stranded DNA and generates a novel secondmessenger 2′-5′cGMP-AMP (cGAMP). cGAMP binds stimulator of IFN genes (STING), causing its dimerization leading to activation of TBK1/IRF3 and IKK/NF-κB, pathways resulting in the induction of type I IFNs and proinflammatory cytokines, respectively (1). DNases outside cells (DNase I), within the phagolysosomal compartment (DNase II) or cytosol (DNase III/Trex1), ensure that in healthy individuals self nucleic acids do not trigger DNA sensors (2). Inappropriate clearance of DNA and its subsequent detection by DNA sensors underlies the pathogenesis of debilitating human diseases, such as Aicardi-Goutiéres syndrome (3). A subset of Aicardi-Goutiéres syndrome patients have mutations in Trex1, a 3′-5′ exonuclease that degrades DNA, which accumulates from endogenous retroelements (4, 5).Gain-of-function (GOF) mutations in components of RNA and DNA sensing pathways can also result in severe autoinflammatory and autoimmune diseases. Examples include the GOF mutations in DDX58 (RIG-I) and ...

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

“…When the STING signal is stimulated, apoptosis occurs more frequently in normal or cancerous T cells (119). Also, bone-marrow chimeras and gene-knockout studies have shown that T cells defect in SAVI are not associated with type-I IFN signaling or cGAS (213,214). Localization of STING at the Golgi can cause delay of T-cell mitosis and reduced proliferation independently of IRF3 and TBK1 (215).…”

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

“…The activation of STING confers to the host immunity and plays a critical role in removing multiple pathogens including both viruses and bacteria [15][16][17]. Meanwhile, uncontrolled and excessive STING activation has been identified to contribute to the progression of autoinflammatory diseases [18,19]. Although the critical and complex role of STING in regulating immune response, which is both detrimental and protective, has been studied for decades, the precise role of STING in the pathological process following SAH has not been clarified.…”

Expression of a constitutively active humanSTINGmutant in hematopoietic cells produces anIfnar1-dependent vasculopathy in mice

“…Furthermore, agonist-mediated mSting protein activation was shown to be toxic to mouse B lymphocytes (Tang et al, 2016). Lastly, Motwani et al (2019) developed two mSting -mutant knock-ins that developed similar phenotypic features as the previous two mSting mutant knock-ins, although these too did not develop acral necrosis (Motwani et al, 2019). They also found that the phenotype was present in the absence of the type I IFN receptor.…”