Endothelial cell expression of a STING gain-of-function mutation initiates pulmonary lymphocytic infiltration
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
Affiliations
Kevin MingJie Gao
Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Kristy Chiang
Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Zhaozhao Jiang
Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Filiz T. Korkmaz
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Harish P. Janardhan
Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Chinmay M. Trivedi
Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Lee J. Quinton
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Sebastien Gingras
Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15260, USA
Katherine A. Fitzgerald
Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Corresponding author
Ann Marshak-Rothstein
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Corresponding author
Summary: 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.
