Nur77 and PPARγ regulate transcription and polarization in distinct subsets of M2-like reparative macrophages during regenerative inflammation

Éva Garabuczi; Nastaran Tarban; Éva Fige; Andreas Patsalos; László Halász; Tímea Szendi-Szatmári; Zsolt Sarang; Róbert Király; Zsuzsa Szondy

doi:10.3389/fimmu.2023.1139204

Nur77 and PPARγ regulate transcription and polarization in distinct subsets of M2-like reparative macrophages during regenerative inflammation

Front Immunol. 2023 Mar 3:14:1139204. doi: 10.3389/fimmu.2023.1139204. eCollection 2023.

Authors

Éva Garabuczi¹, Nastaran Tarban², Éva Fige³, Andreas Patsalos^{4

5}, László Halász^{4

5}, Tímea Szendi-Szatmári⁶, Zsolt Sarang⁷, Róbert Király⁷, Zsuzsa Szondy^{7

8}

Affiliations

¹ Department of Integrative Health Sciences, Institute of Health Sciences, Faculty of Health Sciences, University of Debrecen, Debrecen, Hungary.
² Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
³ Doctoral School of Dental Sciences, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary.
⁴ 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.
⁵ 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.
⁶ Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
⁷ Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
⁸ Section of Dental Biochemistry, Department of Basic Medical Sciences, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary.

Abstract

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-1β 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 PPARγ. 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 PPARγ resulting in enhanced efferocytosis capacity; (2) Nur77 and PPARγ 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-1β 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 PPARγ-expressing subset.

Keywords: Nur77; PPAR gamma; cardiotoxin; efferocytosis; macrophage; polarization; skeletal muscle injury.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Inflammation / metabolism
Interleukin-10* / metabolism
Macrophages / metabolism
Nuclear Receptor Subfamily 4, Group A, Member 1* / metabolism
PPAR gamma* / metabolism
Transcription Factors / metabolism

Substances

Interleukin-10
PPAR gamma
Transcription Factors
Nuclear Receptor Subfamily 4, Group A, Member 1

Grants and funding

This study was supported by the National Research, Development, and Innovation Office-NKFI, Hungary (124244, 138162 and129139). Project no. [121174] has been implemented with the support provided by the Ministry of Culture and Innovation of Hungary from the National Research, Development and Innovation Fund, financed under the [PD_16] funding scheme.