{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:21:39Z","timestamp":1791422499276,"version":"4.3.3"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["AI106839"],"award-info":[{"award-number":["AI106839"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["CA241271"],"award-info":[{"award-number":["CA241271"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008065","name":"Georgia Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Macrophage functional plasticity plays a central role in responding to proinflammatory stimuli. The molecular basis underlying the dynamic phenotypic activation of macrophages, however, remains incompletely understood. In this article, we report that SIRP\u03b1 is a chief negative regulator of proinflammatory macrophage polarization. In response to TLR agonists, proinflammatory cytokines, or canonical M1 stimulation, Src family kinases (SFK) excluding Lyn phosphorylate SIRP\u03b1 ITIMs, leading to the preferential recruitment and activation of SHP-1, but not SHP-2. Solely extracellular ligation of SIRP\u03b1 by CD47 does not greatly induce phosphorylation of SIRP\u03b1 ITIMs, but it enhances proinflammatory stimuli\u2013induced SIRP\u03b1 phosphorylation. Examination of downstream signaling elicited by IFN-\u03b3 and TLR3\/4\/9 agonists found that SIRP\u03b1-activated SHP-1 moderately represses STAT1, NF-\u03baB, and MAPK signaling but markedly inhibits Akt2, resulting in dampened proinflammatory cytokine production and expression of Ag presentation machinery. Pharmacological inhibition of SHP-1 or deficiency of SIRP\u03b1 conversely attenuates SIRP\u03b1-mediated inhibition and, as such, augments macrophage proinflammatory polarization that in turn exacerbates proinflammation in mouse models of type I diabetes and peritonitis. Our results reveal an SFK\u2013SIRP\u03b1\u2013SHP-1 mechanism that fine-tunes macrophage proinflammatory phenotypic activation via inhibition of PI3K\u2013Akt2, which controls the transcription and translation of proinflammatory cytokines, Ag presentation machinery, and other cellular programs.<\/jats:p>","DOI":"10.4049\/jimmunol.2100266","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T18:40:13Z","timestamp":1628102413000},"page":"1419-1427","source":"Crossref","is-referenced-by-count":31,"title":["Non-Lyn Src Family Kinases Activate SIRP\u03b1\u2013SHP-1 to Inhibit PI3K\u2013Akt2 and Dampen Proinflammatory Macrophage Polarization"],"prefix":"10.1093","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6631-6732","authenticated-orcid":false,"given":"Lei","family":"Shi","sequence":"first","affiliation":[{"name":"Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University , Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Bian","sequence":"additional","affiliation":[{"name":"Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University , Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koby","family":"Kidder","sequence":"additional","affiliation":[{"name":"Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University , Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Liang","sequence":"additional","affiliation":[{"name":"Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University , Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University , Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,9,1]]},"reference":[{"key":"2025022610320992300_r1","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1146\/annurev-physiol-022516-034339","article-title":"Macrophage polarization","volume":"79","author":"Murray","year":"2017","journal-title":"Annu. 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