{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T14:57:05Z","timestamp":1793717825587,"version":"4.6.1"},"reference-count":40,"publisher":"American Society for Clinical Investigation","issue":"17","license":[{"start":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T00:00:00Z","timestamp":1631059200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["AR072075,AR070549"],"award-info":[{"award-number":["AR072075,AR070549"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010327","name":"Cincinnati Children\u2019s Research Foundation","doi-asserted-by":"crossref","award":["ARC Grant"],"award-info":[{"award-number":["ARC Grant"]}],"id":[{"id":"10.13039\/100010327","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Jellin Family Foundation","award":["Donation"],"award-info":[{"award-number":["Donation"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,8]]},"abstract":"<jats:p>Macrophage activation syndrome (MAS) is a life-threatening cytokine storm complicating systemic juvenile idiopathic arthritis (SJIA) driven by IFN-\u03b3. SJIA and MAS are also associated with an unexplained emerging inflammatory lung disease (SJIA-LD), with our recent work supporting pulmonary activation of IFN-\u03b3 pathways pathologically linking SJIA-LD and MAS. Our objective was to mechanistically define the potentially novel observation of pulmonary inflammation in the TLR9 mouse model of MAS. In acute MAS, lungs exhibit mild but diffuse CD4-predominant, perivascular interstitial inflammation with elevated IFN-\u03b3, IFN-induced chemokines, and alveolar macrophage (AM\u03d5) expression of IFN-\u03b3\u2013induced genes. Single-cell RNA sequencing confirmed IFN-driven transcriptional changes across lung cell types with myeloid expansion and detection of MAS-specific macrophage populations. Systemic MAS resolution was associated with increased AM\u03d5 and interstitial lymphocytic infiltration. AM\u03d5 transcriptomic analysis confirmed IFN-\u03b3\u2013induced proinflammatory polarization during acute MAS, which switches toward an antiinflammatory phenotype after systemic MAS resolution. Interestingly, recurrent MAS led to increased alveolar inflammation and lung injury, and it reset AM\u03d5 polarization toward a proinflammatory state. Furthermore, in mice bearing macrophages insensitive to IFN-\u03b3, both systemic features of MAS and pulmonary inflammation were attenuated. These findings demonstrate that experimental MAS induces IFN-\u03b3\u2013driven pulmonary inflammation replicating key features of SJIA-LD and provides a model system for testing potentially novel treatments directed toward SJIA-LD.<\/jats:p>","DOI":"10.1172\/jci.insight.147593","type":"journal-article","created":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T12:01:50Z","timestamp":1627387310000},"source":"Crossref","is-referenced-by-count":40,"title":["IFN-\u03b3 is essential for alveolar macrophage\u2013driven pulmonary inflammation in macrophage activation syndrome"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3765-5791","authenticated-orcid":true,"given":"Denny K.","family":"Gao","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, Ohio, 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