GSE212371
TNFa and IFN? cooperate for efficient pro- to anti-inflammatory transition of macrophages during muscle regeneration (scRNA-Seq)
IFN? is traditionally known as a pro-inflammatory cytokine with diverse roles in antimicrobial and antitumor immunity. Yet, findings regarding its sources and functions during the regeneration process following a sterile injury are conflicting. Here, we show that natural killer (NK) cells are the main source of IFN? in regenerating muscle. Beyond this cell population, IFN? production is limited to a small population of T cells. We further show that NK cells do not play a major role in muscle regeneration following an acute injury or in dystrophic mice. Surprisingly, the absence of IFN? per se also has no effect on muscle regeneration following an acute injury. However, the role of IFN? is partially unmasked when TNFa is also neutralized, suggesting a compensatory mechanism. Using transgenic mice, we showed that conditional inhibition of IFNGR1 signaling in muscle stem cells or fibro-adipogenic progenitors does not play a major role in muscle regeneration. In contrast to common belief, we found that IFN? is not present in the early inflammatory phase of the regeneration process, but rather peaks when macrophages are acquiring an anti-inflammatory phenotype. Our further transcriptomic analysis suggests that IFN? cooperates with TNFa to regulate the transition of macrophages from pro- to anti-inflammatory. The absence of the cooperative effect of these cytokines on macrophages, however, does not result in significant regeneration impairment likely due to the presence of other compensatory mechanisms. Our findings support the arising view of IFN? as a pleiotropic inflammatory regulator rather than an inducer of the inflammatory response. Overall design: Dissection of the role of IFN? in muscle regeneration and fibrosis