Expression of a STING Gain-of-function Mutation in Endothelial Cells Initiates Lymphocytic Infiltration of the Lungs

Kevin MingJie Gao; Kristy Chiang; Filiz T Korkmaz; Harish Palleti Janardhan; Chinmay M Trivedi; Lee J Quinton; Sebastien Gingras; Katherine A Fitzgerald; Ann Marshak-Rothstein

doi:10.1101/2023.07.27.550897

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Expression of a STING Gain-of-function Mutation in Endothelial Cells Initiates Lymphocytic Infiltration of the Lungs

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Expression of a STING Gain-of-function Mutation in Endothelial Cells Initiates Lymphocytic Infiltration of the Lungs

Kevin MingJie Gao, Kristy Chiang, Filiz T Korkmaz, Harish Palleti Janardhan, Chinmay M Trivedi, Lee J Quinton, Sebastien Gingras, Katherine A Fitzgerald and Ann Marshak-Rothstein

bioRxiv : the preprint server for biology

Cold Spring Harbor Laboratory

07/27/2023

DOI: 10.1101/2023.07.27.550897

PMCID: PMC10402179

PMID: 37547024

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https://doi.org/10.1101/2023.07.27.550897View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Patients afflicted with 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 the initiation of ILD. To identify STING-expressing non-hematopoietic cell types relevant to ILD, we generated a conditional knock-in (CKI) model in which expression of the VM allele was directed to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted expression of the mutant allele resulted in the recruitment of immune cells to the lung 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 SAVI patients or patients afflicted with other ILD-related disorders. Summary Patients with STING gain-of-function (GOF) mutations develop life-threatening lung autoinflammation. In this study, Gao et al. utilize a mouse model of conditional STING GOF to demonstrate a role for endothelial STING GOF in initiating immune cell recruitment into lung tissues of SAVI mice.

Details

Title: Subtitle: Expression of a STING Gain-of-function Mutation in Endothelial Cells Initiates Lymphocytic Infiltration of the Lungs
Creators: Kevin MingJie Gao
Kristy Chiang
Filiz T Korkmaz
Harish Palleti Janardhan
Chinmay M Trivedi
Lee J Quinton
Sebastien Gingras
Katherine A Fitzgerald
Ann Marshak-Rothstein
Resource Type: Preprint
Publication Details: bioRxiv : the preprint server for biology
DOI: 10.1101/2023.07.27.550897
PMID: 37547024
PMCID: PMC10402179
Publisher: Cold Spring Harbor Laboratory; United States
Grant note: R01 HL141377 / NHLBI NIH HHS R01 HL118100 / NHLBI NIH HHS T32 AI132152 / NIAID NIH HHS
Language: English
Date posted: 07/27/2023
Academic Unit: Microbiology and Immunology
Record Identifier: 9984696851802771

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