PMID- 36936920 OWN - NLM STAT- MEDLINE DCOM- 20230327 LR - 20230328 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Nur77 and PPARgamma regulate transcription and polarization in distinct subsets of M2-like reparative macrophages during regenerative inflammation. PG - 1139204 LID - 10.3389/fimmu.2023.1139204 [doi] LID - 1139204 AB - Macrophage polarization is a process whereby macrophages develop a specific phenotype and functional response to different pathophysiological stimuli and tissue environments. In general, two main macrophage phenotypes have been identified: inflammatory (M1) and alternatively activated (M2) macrophages characterized specifically by IL-1beta and IL-10 production, respectively. In the cardiotoxin-induced skeletal muscle injury model bone marrow-derived macrophages (BMDMs) play the central role in regulating tissue repair. Bone marrow-derived monocytes arriving at the site of injury differentiate first to M1 BMDMs that clear cell debris and trigger proliferation and differentiation of the muscle stem cells, while during the process of efferocytosis they change their phenotype to M2 to drive resolution of inflammation and tissue repair. The M2 population is formed from at least three distinct subsets: antigen presenting, resolution-related and growth factor producing macrophages, the latest ones expressing the transcription factor PPARgamma. Nuclear receptor subfamily 4 group A member 1 (NR4A1; also termed Nur77) transcription factor is expressed as an early response gene, and has been shown to suppress the expression of pro-inflammatory genes during efferocytosis. Here we demonstrate that (1) Nur77 null BMDMs are characterized by elevated expression of PPARgamma resulting in enhanced efferocytosis capacity; (2) Nur77 and PPARgamma regulate transcription in different subsets of M2 skeletal muscle macrophages during muscle repair; (3) the loss of Nur77 prolongs M1 polarization characterized by increased and prolonged production of IL-1beta by the resolution-related macrophages normally expressing Nur77; whereas, in contrast, (4) it promotes M2 polarization detected via the increased number of IL-10 producing CD206(+) macrophages generated from the PPARgamma-expressing subset. CI - Copyright (c) 2023 Garabuczi, Tarban, Fige, Patsalos, Halasz, Szendi-Szatmari, Sarang, Kiraly and Szondy. FAU - Garabuczi, Eva AU - Garabuczi E AD - Department of Integrative Health Sciences, Institute of Health Sciences, Faculty of Health Sciences, University of Debrecen, Debrecen, Hungary. FAU - Tarban, Nastaran AU - Tarban N AD - Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. FAU - Fige, Eva AU - Fige E AD - Doctoral School of Dental Sciences, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary. FAU - Patsalos, Andreas AU - Patsalos A AD - Department of Medicine, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States. AD - Department of Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States. FAU - Halasz, Laszlo AU - Halasz L AD - Department of Medicine, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States. AD - Department of Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States. FAU - Szendi-Szatmari, Timea AU - Szendi-Szatmari T AD - Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. FAU - Sarang, Zsolt AU - Sarang Z AD - Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. FAU - Kiraly, Robert AU - Kiraly R AD - Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. FAU - Szondy, Zsuzsa AU - Szondy Z AD - Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. AD - Section of Dental Biochemistry, Department of Basic Medical Sciences, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230303 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 130068-27-8 (Interleukin-10) RN - 0 (PPAR gamma) RN - 0 (Transcription Factors) RN - 0 (Nuclear Receptor Subfamily 4, Group A, Member 1) SB - IM MH - Humans MH - Inflammation/metabolism MH - *Interleukin-10/metabolism MH - Macrophages/metabolism MH - *PPAR gamma/metabolism MH - Transcription Factors/metabolism MH - *Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism PMC - PMC10020500 OTO - NOTNLM OT - Nur77 OT - PPAR gamma OT - cardiotoxin OT - efferocytosis OT - macrophage OT - polarization OT - skeletal muscle injury COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/03/21 06:00 MHDA- 2023/03/22 06:00 PMCR- 2023/01/01 CRDT- 2023/03/20 03:56 PHST- 2023/01/06 00:00 [received] PHST- 2023/02/22 00:00 [accepted] PHST- 2023/03/20 03:56 [entrez] PHST- 2023/03/21 06:00 [pubmed] PHST- 2023/03/22 06:00 [medline] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1139204 [doi] PST - epublish SO - Front Immunol. 2023 Mar 3;14:1139204. doi: 10.3389/fimmu.2023.1139204. eCollection 2023.