Radioresistant cells initiate lymphocyte-dependent lung inflammation and IFNγ-dependent mortality in STING gain-of-function mice

Abstract

Pediatric patients with constitutively active mutations in the cytosolic double-stranded-DNA-sensing adaptor STING develop an autoinflammatory syndrome known as STING-associated vasculopathy with onset in infancy (SAVI). SAVI patients have elevated interferon-stimulated gene expression and suffer from interstitial lung disease (ILD) with lymphocyte predominate bronchus-associated lymphoid tissue (BALT). Mice harboring SAVI mutations (STING V154M [VM]) that recapitulate human disease also develop lymphocyte-rich BALT. Ablation of either T or B lymphocytes prolongs the survival of SAVI mice, but lung immune aggregates persist, indicating that T cells and B cells can independently be recruited as BALT. VM T cells produced IFNγ, and IFNγR deficiency prolonged the survival of SAVI mice; however, T-cell-dependent recruitment of infiltrating myeloid cells to the lung was IFNγ independent. Lethally irradiated VM recipients fully reconstituted with wild type bone-marrow-derived cells still developed ILD, pointing to a critical role for VM-expressing radioresistant parenchymal and/or stromal cells in the recruitment and activation of pathogenic lymphocytes. We identified lung endothelial cells as radioresistant cells that express STING. Transcriptional analysis of VM endothelial cells revealed up-regulation of chemokines, proinflammatory cytokines, and genes associated with antigen presentation. Together, our data show that VM-expressing radioresistant cells play a key role in the initiation of lung disease in VM mice and provide insights for the treatment of SAVI patients, with implications for ILD associated with other connective tissue disorders.

The commonTMEM173 HAQ, AQalleles rescue CD4 T cellpenia, restore T-regs, and preventSAVI (N153S)inflammatory disease in mice

“…SAVI was characterized as type I interferonopathy 16 . However, several studies showed that type I IFN signaling and IRF3 activation were dispensable for SAVI disease 13,14,47,48 . AQ allele prevents SAVI disease (Figure 4).…”

“…IFN was proposed to drive SAVI disease 15,35,48 . We confirmed that WT/SAVI CD4 T cells were enriched with IFN + cells (Figure 6A).…”

A path towards personalized medicine for autoinflammatory and related diseases

“…Thus, to attempt gene therapy to correct a disease-causing mutation, the appropriate target cell must first be identified, and the best option for such preliminary studies is an animal model. Indeed, data from bone marrow chimaera experiments in a mouse model of SAVI point to a critical role for mutant STING-expressing radioresistant parenchymal and/or stromal cells in the recruitment and activation of pathogenic lymphocytes in SAVI-associated lung disease 45 , as well as a role for type II interferon (IFNγ) receptor signalling 45 , 46 . In addition to clinical phenotyping and cell culture experiments to study disease-causing mutations, the path towards the development of effective personalized therapies should ideally include extensive and rigorous studies of disease-causing mutations in animals, such as in mice that express human versions of the disease-causing mutant proteins 16 , 21 , 22 , 47 .…”

Tissue inflammation induced by constitutively active STING is mediated by enhanced TNF signaling

“…Gain-of-function mutations of human STING1 cause STING-associated vasculopathy with onset in infancy (SAVI), which is characterized by severe interstitial lung disease, T cell lymphopenia, skin inflammation and perturbed IFN- and NF-κB-driven signaling (Clarke et al, 2020; Liu et al, 2014; Picard et al, 2016; Tang et al, 2020). Genetically induced chronic activation of STING results in comparable severe systemic autoinflammatory symptoms in the murine organism (Bennion et al, 2019, 2020; Gao et al, 2022; Luksch et al, 2019; MacLauchlan et al, 2023; Martin et al, 2019; Motwani et al, 2019; Platt et al, 2021; Shmuel-Galia et al, 2021; Siedel et al, 2020; Stinson et al, 2022; Szego et al, 2022; Warner et al, 2017). We previously established a SAVI mouse model, by knocking in the disease causing variant N153S into the endogenous murine Sting1 gene (STING ki) resulting in T cell lymphopenia, interstitial lung disease and systemic autoinflammation (Luksch et al, 2019).…”