Exosomal miR-146a-5p mediates macrophage polarization through TRAF6/NF-κB signaling in endometriosis

Exosomes play significant roles in immune responses, neurogenesis, and angiogenesis, directly impacting the progression and symptomatic manifestations of endometriosis. This study aimed to investigate the role of exosomal miR-146a-5p in the pathogenesis of endometriosis. Through high-throughput RNA sequencing and qRT‒PCR, we revealed significant upregulation of miR-146a-5p in ectopic endothelial tissues, and Gene Ontology (GO) analysis revealed that miR-146a-5p has only one target, TNF receptor associated factor 6 (TRAF6). KEGG pathway analysis indicated that the NF-κB signaling pathway is the key signaling pathway involved. The study revealed that the upregulation of miR-146a-5p in macrophages is associated with an increase in M2 macrophages. In the U937 macrophage line, miR-146a-5p was capable of suppressing TRAF6 expression, which in turn decreased the phosphorylation level of NF-κB, whereas the overexpression of TRAF6 increased the activity of this pathway. Furthermore, we incorporated the NF-κB inhibitor EVP4593 into a macrophage culture, which revealed that blocking this pathway significantly induced both M1 and M2 macrophage polarization, particularly enhancing M2 polarization. In conclusion, exosome-derived miR-146a-5p promotes M2 polarization of macrophages by regulating the TRAF6/NF-κB pathway in endometriosis.