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

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

Cell reports (2024-04-16)
Kevin MingJie Gao, Kristy Chiang, Zhaozhao Jiang, Filiz T Korkmaz, Harish P Janardhan, Chinmay M Trivedi, Lee J Quinton, Sebastien Gingras, Katherine A Fitzgerald, Ann Marshak-Rothstein
ABSTRACT

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 STINGV154M 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti- STING, clone 41 Antibody, clone 41, 0.5 mg/mL, from rat
Sigma-Aldrich
Tamoxifen, ≥99%