The M2a macrophage subset may be critically involved in the fibrogenesis of endometriosis in mice

Research question Recent research has shown that endometriotic lesions are essentially wounds that undergo repeated tissue injury and repair, which results in epithelial–mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, smooth muscle metaplasia and ultimately fibrosis. Macrophages are a key regulator of tissue repair and fibrogenesis. But do macrophages also play a role in fibrogenesis of endometriosis, and, if yes, which subset of macrophages? Design To elucidate the role of macrophages in fibrogenesis of endometriosis, we conducted three experiments in mice. In experiment 1, endometriotic tissue samples from female Balb/C mice with induced endometriosis were serially harvested to evaluate the role of macrophages in fibrogenesis. In experiments 2 and 3, female transgenic mice (C57BL/6J background) expressing the human diphtheria toxin receptor under the control of the CD11b promoter had macrophage depletion by diphtheria toxin injection after induction of endometriosis. Additionally, in experiment 3, adoptive transfer of different subsets of macrophage was carried out after macrophage depletion. Results Lesional infiltration of M2 macrophages increased progressively as lesions progressed undisturbed, concomitant with progressive epithelial–mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation and fibrosis. Macrophage depletion after induction of endometriosis significantly reduced lesional infiltration of total macrophages, significantly reduced lesional infiltration of M2 macrophages and significantly reduced lesional fibrotic content and lesion weight (P < 0.05). Finally, adoptive transfer of M2a, but not M1 or M2c macrophages, systemically after macrophage depletion significantly increased the extent of fibrosis in lesions (P = 1.6 × 10−10). Conclusions The identification of a particular macrophage subset in fibrogenesis of endometriosis should further help to shed new light on the pathophysiology of endometriosis.