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.

Keywords: STING-associated vasculopathy with onset in infancy; interferons; nucleic acid sensing.

Figure 1

STING Signaling. (A,B) Upon DNA sensing by cGAS, cGAMP binds to wild-type (WT) STING. STING trafficks then to the Golgi and undergoes post-translational modifications. STING activation in the Golgi leads to type I interferon (IFN) production, NF-κβ pathway activation, and cell death induction through endoplasmic reticulum (ER) stress. STING trafficking is normally controlled through retro-transport to the ER via COPA and by trafficking to the autophagosome, where it is degraded. (C) When affected by a gain-of-function mutation, STING is constitutively activated in the Golgi in a cGAMP-independent manner and enhances constitutive type I IFN production through IRF3 phosphorylation and inflammatory cytokine production by activating the NF-κβ pathway. STING constitutive activation in the Golgi also induces ER stress, which can further lead to cell death. Finally, reduction of STING clearance by autophagy is described in the context of STING gain-of-function. Adapted from Frémond et al., J Clin Immunol, 2021. Created with biorender.com, accessed on 26 November 2021, last accessed on 13 January 2022.

Figure 2

Schematic Representation of STING Protein Encoded by STING1 Gene and Localization of Disease-Causing Mutations. * indicates homozygous mutations.

Figure 3

Representative Lung Imaging and Pathology in SAVI. (A,B) Coronal and axial image of a chest computed tomography (CT) scan from a SAVI patient showing interstitial lung disease with ground glass opacities, cysts, and septal wall thickening. (C,D) Lung tissue section biopsy from a SAVI patient showing lymphoid infiltrate consisting mainly of CD20+ cells. Original magnification: ×40 (C; scale bars, 100 µm), ×10 (D; scale bars, 400 µm) Adapted from Jeremiah et al., J Clin Invest, 2014 and Frémond et al., J Allergy Clin Immunol Pract, 2021.