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 |
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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). Published by PNAS. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-f304cb0a57e4209756e68d9d9234ee9c26c6aa25bf9b95fa8a60118a5dce6fde3</citedby><cites>FETCH-LOGICAL-c421t-f304cb0a57e4209756e68d9d9234ee9c26c6aa25bf9b95fa8a60118a5dce6fde3</cites><orcidid>0000-0001-5855-1006</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9231608/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9231608/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35696583$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gao, Kevin MingJie</creatorcontrib><creatorcontrib>Motwani, Mona</creatorcontrib><creatorcontrib>Tedder, Thomas</creatorcontrib><creatorcontrib>Marshak-Rothstein, Ann</creatorcontrib><creatorcontrib>Fitzgerald, Katherine A</creatorcontrib><title>Radioresistant cells initiate lymphocyte-dependent lung inflammation and IFNγ-dependent mortality in STING gain-of-function mice</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><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.</description><subject>Ablation</subject><subject>Animals</subject><subject>Antigen presentation</subject><subject>Antigens</subject><subject>Biological Sciences</subject><subject>Bone marrow</subject><subject>Bronchus</subject><subject>Cell activation</subject><subject>Chemokines</subject><subject>Child</subject><subject>Connective tissues</subject><subject>Cytokines</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - immunology</subject><subject>Endothelial Cells - radiation effects</subject><subject>Gain of Function Mutation</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Interferon</subject><subject>Interferon-gamma - genetics</subject><subject>Interferon-gamma - metabolism</subject><subject>Lung diseases</subject><subject>Lung Diseases, Interstitial - genetics</subject><subject>Lung Diseases, Interstitial - immunology</subject><subject>Lymphocyte Depletion</subject><subject>Lymphocytes</subject><subject>Lymphocytes B</subject><subject>Lymphocytes T</subject><subject>Lymphoid tissue</subject><subject>Lymphoid Tissue - immunology</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mutation</subject><subject>Myeloid cells</subject><subject>Patients</subject><subject>Pediatrics</subject><subject>Radiation Tolerance</subject><subject>Recruitment</subject><subject>Stromal cells</subject><subject>Survival</subject><subject>T-Lymphocytes - immunology</subject><subject>Vascular diseases</subject><subject>Vascular Diseases - genetics</subject><subject>Vascular Diseases - immunology</subject><subject>γ-Interferon</subject><issn>0027-8424</issn><issn>1091-6490</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1v1DAQhi0EokvhzA1F4sIlrT9iJ74goYqWlaoiQTlbs8546yqxQ-wg7ZHf1P_R34SXllI4jTTzzDsfLyGvGT1itBXHU4B0xDnlgreM6SdkxahmtWo0fUpWlPK27hreHJAXKV1TSrXs6HNyIKTSSnZiRX5-gd7HGZNPGUKuLA5Dqnzw2UPGatiN01W0u4x1jxOGHgszLGFbEDfAOEL2MVQQ-mp9enF784ga45xh8HlX0Orr5frirNqCD3V0tVuC_d03eosvyTMHQ8JX9_GQfDv9eHnyqT7_fLY--XBe24azXDtBG7uhIFtsONWtVKi6XveaiwZRW66sAuBy4_RGSwcdKMpYB7K3qFyP4pC8v9Odls2IJRvyDIOZZj_CvDMRvPm3EvyV2cYfpkxginZF4N29wBy_L5iyGX3a_wsCxiUZrlolJadCF_Ttf-h1XOZQzitUxzqtpdwLHt9Rdo4pzegelmHU7O01e3vNX3tLx5vHNzzwf_wUvwDX26V6</recordid><startdate>20220621</startdate><enddate>20220621</enddate><creator>Gao, Kevin MingJie</creator><creator>Motwani, Mona</creator><creator>Tedder, Thomas</creator><creator>Marshak-Rothstein, Ann</creator><creator>Fitzgerald, Katherine A</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5855-1006</orcidid></search><sort><creationdate>20220621</creationdate><title>Radioresistant cells initiate lymphocyte-dependent lung inflammation and IFNγ-dependent mortality in STING gain-of-function mice</title><author>Gao, Kevin MingJie ; 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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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>35696583</pmid><doi>10.1073/pnas.2202327119</doi><orcidid>https://orcid.org/0000-0001-5855-1006</orcidid><oa>free_for_read</oa></addata></record> |
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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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