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

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.

Regulation of polarization of lung macrophages by Nur77/Nr4a1

“…17 Moreover, Nur77/NR4A1 can interact with other transcription factors, such as peroxisome proliferator-activated receptor gamma (PPARγ) and Kruppel-like factor 4 (KLF4), to promote their transcriptional activity and amplify the M2 polarization response. 18 Additionally, Nur77/NR4A1 has been implicated in enhancing the phagocytic activity of M2 macrophages. It has been shown to regulate the expression of scavenger receptors, such as CD36 and CD163, which are involved in the recognition and uptake of apoptotic cells and debris.…”

“…Unraveling the underlying mechanisms and identifying specific target genes will shed light on the therapeutic potential of Nur77/NR4A1 modulation in conditions where promoting M2 polarization is beneficial. 18…”

“…In lung injury models, Nur77/NR4A1 has been associated with the regulation of inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), suggesting its role in promoting M1 polarization. 7,18 Furthermore, Nur77/NR4A1 has been implicated in the resolution phase of lung injury, where the immune response shifts towards tissue repair and anti-inflammatory processes. During this phase, macrophages adopt an M2like phenotype to facilitate tissue healing and remodeling.…”

“…It has been reported to play a role in lipid metabolism and cholesterol efflux in macrophages, which are essential processes for foam cell formation and atherosclerosis development. 7 Additionally, Nur77 has been shown to promote phagocytosis and clearance of apoptotic cells by macrophages, contributing to tissue homeostasis and resolution of inflammation 8 . Overall, Nur77/NR4A1 is a versatile transcription factor that plays a role in regulating immune responses, including macrophage function and polarization.…”

Loss of adenosine A3 receptors accelerates skeletal muscle regeneration in mice following cardiotoxin-induced injury

“…The composition of the appearing reparative Ly6C low MΦs is dynamically changing during the repair process, and they can be divided at least into three subgroups: growth factor-expressing, resolution-related and antigen-presenting cells [ 19 ]. Since some of them specifically express certain genes, the loss of the proteins encoded by them individually affects the further conversion (for example the conversion into CD206 + cells) of the different reparative macrophage subpopulations [ 20 – 22 ].…”