{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T13:51:11Z","timestamp":1784641871727,"version":"3.55.0"},"reference-count":80,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2020,11,1]],"date-time":"2020-11-01T00:00:00Z","timestamp":1604188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI106839"],"award-info":[{"award-number":["AI106839"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>A hallmark of secondary hemophagocytic lymphohistiocytosis (sHLH), a severe form of cytokine storm syndrome, is the emergence of overactivated macrophages that engulf healthy host blood cells (i.e., hemophagocytosis) and contribute to the dysregulated inflammation-driven pathology. In this study, we show that depleting SIRP\u03b1 (SIRP\u03b1\u2212\/\u2212) in mice during TLR9-driven inflammation exacerbates and accelerates the onset of fulminant sHLH, in which systemic hemophagocytosis, hypercytokinemia, consumptive cytopenias, hyperferritinemia, and other hemophagocytic lymphohistiocytosis hallmarks were apparent. In contrast, mice expressing SIRP\u03b1, including those deficient of the SIRP\u03b1 ligand CD47 (CD47\u2212\/\u2212), do not phenocopy SIRP\u03b1 deficiency and fail to fully develop sHLH, albeit TLR9-inflamed wild-type and CD47\u2212\/\u2212 mice exhibited hemophagocytosis, anemia, and splenomegaly. Although IFN-\u03b3 is largely considered a driver of hemophagocytic lymphohistiocytosis pathology, IFN-\u03b3 neutralization did not preclude the precipitation of sHLH in TLR9-inflamed SIRP\u03b1\u2212\/\u2212 mice, whereas macrophage depletion attenuated sHLH in SIRP\u03b1\u2212\/\u2212 mice. Mechanistic studies confirmed that SIRP\u03b1 not only restrains macrophages from acquiring a hemophagocytic phenotype but also tempers their proinflammatory cytokine and ferritin secretion by negatively regulating Erk1\/2 and p38 activation downstream of TLR9 signaling. In addition to TLR9 agonists, TLR2, TLR3, or TLR4 agonists, as well as TNF-\u03b1, IL-6, or IL-17A, but not IFN-\u03b3, similarly induced sHLH in SIRP\u03b1\u2212\/\u2212 mice but not SIRP\u03b1+ mice. Collectively, our study suggests that SIRP\u03b1 plays a previously unappreciated role in sHLH\/cytokine storm syndrome pathogenesis by preventing macrophages from becoming both hemophagocytic and hyperactivated under proinflammation.<\/jats:p>","DOI":"10.4049\/jimmunol.2000652","type":"journal-article","created":{"date-parts":[[2020,10,7]],"date-time":"2020-10-07T19:30:13Z","timestamp":1602099013000},"page":"2821-2833","source":"Crossref","is-referenced-by-count":22,"title":["Inflammation Unrestrained by SIRP\u03b1 Induces Secondary Hemophagocytic Lymphohistiocytosis Independent of IFN-\u03b3"],"prefix":"10.1093","volume":"205","author":[{"given":"Koby","family":"Kidder","sequence":"first","affiliation":[{"name":"Program of Immunology and Cellular Biology, Department of Biology, Georgia State University , Atlanta, GA 30302"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Bian","sequence":"additional","affiliation":[{"name":"Program of Immunology and Cellular Biology, Department of Biology, Georgia State University , Atlanta, GA 30302"},{"name":"Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, GA 30302"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Shi","sequence":"additional","affiliation":[{"name":"Program of Immunology and Cellular Biology, Department of Biology, Georgia State University , Atlanta, GA 30302"},{"name":"Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, GA 30302"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Program of Immunology and Cellular Biology, Department of Biology, Georgia State University , Atlanta, GA 30302"},{"name":"Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, GA 30302"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,11,15]]},"reference":[{"key":"2025030417505707700_r1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev-pathol-020117-043625","article-title":"Hemophagocytic lymphohistiocytosis","volume":"13","author":"Al-Samkari","year":"2018","journal-title":"Annu. 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