Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

Abstract

STING-associated vasculopathy with onset in infancy (SAVI) is a type I interferonopathy caused by gain-of-function mutations in STING1 encoding stimulator of interferon genes (STING) protein. SAVI is characterized by severe inflammatory lung disease, a feature not observed in previously described type I interferonopathies i.e., Mendelian autoinflammatory disorders defined by constitutive activation of the type I interferon (IFN) pathway. Molecular defects in nucleic acid metabolism or sensing are central to the pathophysiology of these diseases, with such defects occurring at any step of the tightly regulated pathway of type I IFN production and signaling (e.g., exonuclease loss of function, RNA-DNA hybrid accumulation, constitutive activation of adaptor proteins such as STING). Among over 30 genotypes, SAVI and COPA syndrome, whose pathophysiology was recently linked to a constitutive activation of STING signaling, are the only type I interferonopathies presenting with predominant lung involvement. Lung disease is the leading cause of morbidity and mortality in these two disorders which do not respond to conventional immunosuppressive therapies and only partially to JAK1/2 inhibitors. In human silicosis, STING-dependent sensing of self-DNA following cell death triggered by silica exposure has been found to drive lung inflammation in mice and human models. These recent findings support a key role for STING and nucleic acid sensing in the homeostasis of intrinsic pulmonary inflammation. However, mechanisms by which monogenic defects in the STING pathway lead to pulmonary damages are not yet fully elucidated, and an improved understanding of such mechanisms is fundamental to improved future patient management. Here, we review the recent insights into the pathophysiology of SAVI and outline our current understanding of self-nucleic acid-mediated lung inflammation in humans.

Phenotypic spectrum in recessive STING-associated vasculopathy with onset in infancy: Four novel cases and analysis of previously reported cases

“…Type I IFNs induced by STING activation bind to receptors IFNAR1/2, subsequently activating the Janus kinases (JAK)/signal transducer and activator of transcription (STAT) pathway. In this context, JAK inhibitors have been applied in SAVI patients ( 9 ). The selective oral JAK1/2 inhibitor ruxolitinib showed marked positive effects on lung and cutaneous pathologies in AD SAVI without significant side effects ( 46 ).…”

“…Since its first description in 2014 ( 2 ), more than 20 cases with autosomal dominant SAVI have been described. A total of 16 different heterozygous, causative missense variants in STING1 have been reported, most of which have arosen de novo ( 2 , 8 , 9 ). Unfortunately, most of them are not listed in public databases (e.g., ClinVar) ( 10 ).…”

Activation of STING Based on Its Structural Features

“…For instance, STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease driven by gain-of-function mutations in STING, first reported in 2014 ( 60 ). In the following several years, many SAVI cases were reported, and the associated mutants are located in multiple sites of the STING protein ( 61 , 62 ). These mutants could be divided into at least four clusters according to their locations in the STING protein structure ( Figure 7 ).…”

Inhibitory targeting cGAS-STING-TBK1 axis: Emerging strategies for autoimmune diseases therapy

“…Mutations in exon 5 of STING lead to functional activation of STING, resulting in the excessive STING-induced IFN signaling, causing a disorder termed SAVI including recurrent fever, ulcerative skin lesions, vasculitis, and interstitial lung disease ( Figure 5B ) ( 18 , 20 ). Mutant residues are located in two separate regions on STING, the connector helix loop (N154S, V155M, G158A, G166E, H72N, and V147M/L) and the polymerization interface (C206Y/G, G207E, F279L, R281Q/W, and R284G/S) ( 86 – 89 ). Mutations in the regions can spontaneously rotate around the connected helix loop by inducing the LBD allosteric activation, or by promoting the STING polymerization, thereby triggering the ligand-independent activation of STING ( 50 , 58 ).…”