TNFα and IFNγ cooperate for efficient pro- to anti-inflammatory transition of macrophages during muscle regeneration.

Autor:	Babaeijandaghi F; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada., Paiero A; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.; Faculty of Medicine, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada., Long R; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.; Department of Integrative Biology, University of Guelph, Guelph, ON, N1G 2W1, Canada., Tung LW; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada., Smith SP; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada., Cheng R; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada., Smandych J; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada., Kajabadi N; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada., Chang CK; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada., Ghassemi A; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada., Kennedy WDM; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.; Department of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 0X8, Canada., Soliman H; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.; Aspect Biosystems, Vancouver, BC, V6P 6P2, Canada., Schutz PW; Department of Pathology, University of British Columbia and Vancouver General Hospital, Vancouver, BC, V6T 2B5, Canada., Rossi FMV; Biomedical Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Nov; Vol. 119 (44), pp. e2209976119. Date of Electronic Publication: 2022 Oct 24.
DOI:	10.1073/pnas.2209976119
Abstrakt:	IFNγ is traditionally known as a proinflammatory 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 IFNγ in regenerating muscle. Beyond this cell population, IFNγ 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 IFNγ per se also has no effect on muscle regeneration following an acute injury. However, the role of IFNγ is partially unmasked when TNFα 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 IFNγ is not present in the early inflammatory phase of the regeneration process but rather peaks when macrophages are acquiring an anti-inflammatory phenotype. Further transcriptomic analysis suggests that IFNγ cooperates with TNFα to regulate the transition of macrophages from pro- to anti-inflammatory states. 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 IFNγ as a pleiotropic inflammatory regulator rather than an inducer of the inflammatory response.
Databáze:	MEDLINE
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