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

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 fr...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2022-06, Vol.119 (25), p.e2202327119
Hauptverfasser: Gao, Kevin MingJie, Motwani, Mona, Tedder, Thomas, Marshak-Rothstein, Ann, Fitzgerald, Katherine A
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container_title Proceedings of the National Academy of Sciences - PNAS
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creator Gao, Kevin MingJie
Motwani, Mona
Tedder, Thomas
Marshak-Rothstein, Ann
Fitzgerald, Katherine A
description 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.
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2202327119</identifier><identifier>PMID: 35696583</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Ablation ; Animals ; Antigen presentation ; Antigens ; Biological Sciences ; Bone marrow ; Bronchus ; Cell activation ; Chemokines ; Child ; Connective tissues ; Cytokines ; Endothelial cells ; Endothelial Cells - immunology ; Endothelial Cells - radiation effects ; Gain of Function Mutation ; Gene expression ; Humans ; Inflammation ; Interferon ; Interferon-gamma - genetics ; Interferon-gamma - metabolism ; Lung diseases ; Lung Diseases, Interstitial - genetics ; Lung Diseases, Interstitial - immunology ; Lymphocyte Depletion ; Lymphocytes ; Lymphocytes B ; Lymphocytes T ; Lymphoid tissue ; Lymphoid Tissue - immunology ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Mutation ; Myeloid cells ; Patients ; Pediatrics ; Radiation Tolerance ; Recruitment ; Stromal cells ; Survival ; T-Lymphocytes - immunology ; Vascular diseases ; Vascular Diseases - genetics ; Vascular Diseases - immunology ; γ-Interferon</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2022-06, Vol.119 (25), p.e2202327119</ispartof><rights>Copyright National Academy of Sciences Jun 21, 2022</rights><rights>Copyright © 2022 the Author(s). 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subjects Ablation
Animals
Antigen presentation
Antigens
Biological Sciences
Bone marrow
Bronchus
Cell activation
Chemokines
Child
Connective tissues
Cytokines
Endothelial cells
Endothelial Cells - immunology
Endothelial Cells - radiation effects
Gain of Function Mutation
Gene expression
Humans
Inflammation
Interferon
Interferon-gamma - genetics
Interferon-gamma - metabolism
Lung diseases
Lung Diseases, Interstitial - genetics
Lung Diseases, Interstitial - immunology
Lymphocyte Depletion
Lymphocytes
Lymphocytes B
Lymphocytes T
Lymphoid tissue
Lymphoid Tissue - immunology
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mutation
Myeloid cells
Patients
Pediatrics
Radiation Tolerance
Recruitment
Stromal cells
Survival
T-Lymphocytes - immunology
Vascular diseases
Vascular Diseases - genetics
Vascular Diseases - immunology
γ-Interferon
title Radioresistant cells initiate lymphocyte-dependent lung inflammation and IFNγ-dependent mortality in STING gain-of-function mice
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