Endothelial cell expression of a STING gain-of-function mutation initiates pulmonary lymphocytic infiltration.

Patients afflicted with Stimulator of interferon gene (STING) gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STING^V154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in initiating ILD. To identify STING-expressing non-hematopoietic cell types required for the development of ILD, we use a conditional knockin (CKI) model and direct expression of the VM allele to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted VM expression results in enhanced recruitment of immune cells to the lung associated with elevated chemokine expression and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of STING-associated vasculopathy with onset in infancy (SAVI) patients or patients afflicted with other ILD-related disorders. [Display omitted] • STING gain of function (GOF) in endothelial cells promotes BALT formation • Immune cell, epithelial, or fibroblast STING GOF is not sufficient for lung disease • Endothelial STING GOF drives chemokine expression • Ubiquitously targeted STING GOF further exacerbates lung inflammation Patients with STING gain-of-function (GOF) mutations develop a life-threatening lung autoinflammatory disease known as SAVI. In this study, Gao et al. utilize a mouse model of conditional STING GOF to demonstrate the key role of endothelial cells in initiating immune cell recruitment to the lungs of SAVI mice. [ABSTRACT FROM AUTHOR]