Macrophages inhibit and enhance endometriosis depending on their origin

Abstract

Macrophages are intimately involved in the pathophysiology of endometriosis, a chronic inflammatory disorder characterized by the growth of endometrial-like tissue (lesions) outside the uterus. By combining genetic and pharmacological monocyte and macrophage depletion strategies we determined the ontogeny and function of macrophages in a mouse model of induced endometriosis. We demonstrate that lesion-resident macrophages are derived from eutopic endometrial tissue, infiltrating large peritoneal macrophages (LpM) and monocytes. Furthermore, we found endometriosis to trigger continuous recruitment of monocytes and expansion of CCR2+ LpM. Depletion of eutopic endometrial macrophages results in smaller endometriosis lesions, whereas constitutive inhibition of monocyte recruitment significantly reduces peritoneal macrophage populations and increases the number of lesions. Reprogramming the ontogeny of peritoneal macrophages such that embryo-derived LpM are replaced by monocyte-derived LpM decreases the number of lesions that develop. We propose a putative model whereby endometrial macrophages are “proendometriosis” while newly recruited monocyte-derived macrophages, possibly in LpM form, are “antiendometriosis.” These observations highlight the importance of monocyte-derived macrophages in limiting disease progression.

M1 Macrophage-Derived Nanovesicles Repolarize M2 Macrophages for Inhibiting the Development of Endometriosis

“…Our previous study showed that SPMs polarize to M2 macrophages, whereas LPMs tend to polarize to M1 macrophages (22). Consistent with these findings, Hogg et al illustrated the protective effects of monocyte-derived LPM when the peritoneal cavity is challenged with ectopic endometrium (46). In this study, we observed that M2 macrophages were mainly differentiated from SPMs, and these macrophages were susceptible to M1NVs, whereas M2 macrophages differentiated from LPMs were not easily affected by M1NVs.…”

Bioluminescent imaging in induced mouse models of endometriosis reveals differences in four model variations

“…It remains unknown what is different about the lesions that progress or are maintained long-term, and future work should draw comparisons between resolving versus non-resolving mice. Recently, we identified a ‘protective’ population of monocyte-derived large peritoneal macrophages (LpM) in our menses mouse model of endometriosis that limit the development of lesions ( Hogg et al, 2021 ). Using gain- and loss-of-function experiments, we demonstrated that depletion of this population increases development of lesions, whereas reprogramming the peritoneal niche such that embryo-derived LpM are ablated and the niche is repopulated afresh with monocyte-derived LpM, leads to decreased lesion development.…”

Single cell analysis of endometriosis reveals a coordinated transcriptional program driving immunotolerance and angiogenesis across eutopic and ectopic tissues.

“…Among myeloid cell subpopulations, macrophages and DCs have been described as key players in endometriosis pathology 1,2,4 with reports showing endometriosis-related alterations of macrophages 26,52 and DCs 32,33 . However, a comprehensive description of myeloid sub-types that scRNAseq provides was lacking up until now.…”