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Immunol."],"abstract":"<jats:p>Many respiratory viruses cause lung damage that may evolve into acute lung injury (ALI), a cytokine storm, acute respiratory distress syndrome, and ultimately, death. Peroxisome proliferator activated receptor gamma (PPAR\u03b3), a member of the nuclear hormone receptor (NHR) family of transcription factors, regulates transcription by forming heterodimers with another NHR family member, Retinoid X Receptor (RXR). Each component of the heterodimer binds specific ligands that modify transcriptional capacity of the entire heterodimer by recruiting different co-activators\/co-repressors. However, the role of PPAR\u03b3\/RXR ligands in the context of influenza infection is not well understood. PPAR\u03b3 is associated with macrophage differentiation to an anti-inflammatory M2 state. We show that mice lacking the IL-4R\u03b1 receptor, required for M2a macrophage differentiation, are more susceptible to mouse-adapted influenza (A\/PR\/8\/34; \u201cPR8\u201d)-induced lethality. Mice lacking <jats:italic>Ptgs2<\/jats:italic>, that encodes COX-2, a key proinflammatory M1 macrophage mediator, are more resistant. Blocking the receptor for COX-2-induced Prostaglandin E<jats:sub>2<\/jats:sub> (PGE<jats:sub>2<\/jats:sub>) was also protective. Treatment with pioglitazone (PGZ), a PPAR\u03b3 ligand, increased survival from PR8 infection, decreased M1 macrophage gene expression, and increased PPAR\u03b3 mRNA in lungs. Conversely, conditional knockout mice expressing PPAR\u03b3-deficient macrophages were significantly more sensitive to PR8-induced lethality. These findings were extended in cotton rats: PGZ blunted lung inflammation and M1 cytokine gene expression after challenge with non-adapted human influenza. To study mechanisms by which PPAR\u03b3\/RXR transcription factors induce canonical M2a genes, WT mouse macrophages were treated with IL-4 in the absence or presence of rosiglitazone (RGZ; PPAR\u03b3 ligand), LG100754 (LG; RXR ligand), or both. IL-4 dose-dependently induced M2a genes <jats:italic>Arg1<\/jats:italic>, <jats:italic>Mrc1, Chil3, and Retnla<\/jats:italic>. Treatment of macrophages with IL-4 and RGZ and\/or LG differentially affected induction of <jats:italic>Arg1<\/jats:italic> and <jats:italic>Mrc1 vs<\/jats:italic>. <jats:italic>Chil3<\/jats:italic> and <jats:italic>Retnla<\/jats:italic> gene expression. In PPAR\u03b3-deficient macrophages, IL-4 alone failed to induce <jats:italic>Arg1<\/jats:italic> and <jats:italic>Mrc1<\/jats:italic> gene expression; however, concurrent treatment with LG or RGZ + LG enhanced IL-4-induced <jats:italic>Arg1<\/jats:italic> and <jats:italic>Mrc1<\/jats:italic> expression, but to a lower level than in WT macrophages, findings confirmed in the murine alveolar macrophage cell line, MH-S. These findings support a model in which PPAR\u03b3\/RXR heterodimers control IL-4-induced M2a differentiation, and suggest that PPAR\u03b3\/RXR agonists should be considered as important tools for clinical intervention against influenza-induced ALI.<\/jats:p>","DOI":"10.3389\/fimmu.2022.968336","type":"journal-article","created":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T06:00:24Z","timestamp":1660629624000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":33,"title":["Protection against influenza-induced Acute Lung Injury (ALI) by enhanced induction of M2a macrophages: possible role of PPAR\u03b3\/RXR ligands in IL-4-induced M2a macrophage differentiation"],"prefix":"10.3389","volume":"13","author":[{"given":"Archana","family":"Gopalakrishnan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari Ann","family":"Shirey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achsah D.","family":"Keegan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina S.","family":"Boukhvalova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie N.","family":"Vogel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge C. 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