{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:55:40Z","timestamp":1788324940930,"version":"build-2803163510"},"reference-count":82,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T00:00:00Z","timestamp":1626652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>RELM\u03b1 is a small, secreted protein expressed by type 2 cytokine-activated \u201cM2\u201d macrophages in helminth infection and allergy. At steady state and in response to type 2 cytokines, RELM\u03b1 is highly expressed by peritoneal macrophages, however, its function in the serosal cavity is unclear. In this study, we generated RELM\u03b1 TdTomato (Td) reporter\/knockout (R\u03b1<jats:sup>Td<\/jats:sup>) mice and investigated RELM\u03b1 function in IL-4 complex (IL-4c)-induced peritoneal inflammation. We first validated the RELM\u03b1<jats:sup>Td\/Td<\/jats:sup> transgenic mice and showed that IL-4c injection led to the significant expansion of large peritoneal macrophages that expressed Td but not RELM\u03b1 protein, while RELM\u03b1<jats:sup>+\/+<\/jats:sup> mice expressed RELM\u03b1 and not Td. Functionally, RELM\u03b1<jats:sup>Td\/Td<\/jats:sup> mice had increased IL-4 induced peritoneal macrophage responses and splenomegaly compared to RELM\u03b1<jats:sup>+\/+<\/jats:sup> mice. Gene expression analysis indicated that RELM\u03b1<jats:sup>Td\/Td<\/jats:sup> peritoneal macrophages were more proliferative and activated than RELM\u03b1<jats:sup>+\/+<\/jats:sup> macrophages, with increased genes associated with T cell responses, growth factor and cytokine signaling, but decreased genes associated with differentiation and maintenance of myeloid cells. We tested the hypothesis that R\u03b1<jats:sup>Td\/Td<\/jats:sup> macrophages drive aberrant T cell activation using peritoneal macrophage and T cell co-culture. There were no differences in CD4<jats:sup>+<\/jats:sup> T cell effector responses when co-cultured with RELM\u03b1<jats:sup>+\/+<\/jats:sup> or RELM\u03b1<jats:sup>Td\/Td<\/jats:sup> macrophages, however, RELM\u03b1<jats:sup>Td\/Td<\/jats:sup> macrophages were impaired in their ability to sustain proliferation of FoxP3<jats:sup>+<\/jats:sup> regulatory T cells (Treg). Supportive of the <jats:italic>in vitro<\/jats:italic> results, immunofluorescent staining of the spleens revealed significantly decreased FoxP3<jats:sup>+<\/jats:sup> cells in the RELM\u03b1<jats:sup>Td\/Td<\/jats:sup> spleens compared to RELM\u03b1<jats:sup>+\/+<\/jats:sup> spleens. Taken together, these studies identify a new RELM\u03b1 regulatory pathway whereby RELM\u03b1-expressing macrophages directly sustain Treg proliferation to limit type 2 inflammatory responses.<\/jats:p>","DOI":"10.3389\/fimmu.2021.710406","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T12:17:56Z","timestamp":1626697076000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Macrophage-Regulatory T Cell Interactions Promote Type 2 Immune Homeostasis Through Resistin-Like Molecule \u03b1"],"prefix":"10.3389","volume":"12","author":[{"given":"Jiang","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Yong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy 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