Macrophage Migration Inhibitory Factor Is Involved in Ectopic Endometrial Tissue Growth and Peritoneal-Endometrial Tissue Interaction In Vivo: A Plausible Link to Endometriosis Development

Abstract

Pelvic inflammation is a hallmark of endometriosis pathogenesis and a major cause of the disease's symptoms. Abnormal immune and inflammatory changes may not only contribute to endometriosis-major symptoms, but also contribute to ectopic endometrial tissue growth and endometriosis development. A major pro-inflammatory factors found elevated in peritoneal fluid of women with endometriosis and to be overexpressed in peritoneal fluid macrophages and active, highly vascularized and early stage endometriotic lesions, macrophage migration inhibitory factor (MIF) appeared to induce angiogenic and inflammatory and estrogen producing phenotypes in endometriotic cells in vitro and to be a possible therapeutic target in vivo. Using a mouse model where MIF-knock out (KO) mice received intra-peritoneal injection of endometrial tissue from MIF-KO or syngeneic wild type (WT) mice and vice versa, our current study revealed that MIF genetic depletion resulted in a marked reduction ectopic endometrial tissue growth, a disrupted tissue structure and a significant down regulation of the expression of major inflammatory (cyclooxygenease-2), cell adhesion (αv and β3 integrins), survival (B-cell lymphoma-2) and angiogenic (vascular endothelial cell growth) factorsrelevant to endometriosis pathogenesis, whereas MIF add-back to MIF-KO mice significantly restored endometriosis-like lesions number and size. Interestingly, cross-experiments revealed that MIF presence in both endometrial and peritoneal host tissues is required for ectopic endometrial tissue growth and pointed to its involvement in endometrial-peritoneal interactions. This study provides compelling evidence for the role of MIF in endometriosis development and its possible interest for a targeted treatment of endometriosis.

Endometriosis — insights into a multifaceted entity

“…MIF, another cytokine, shows a high level in the peritoneal fluid, in circulation, and in peritoneal macrophages, its secretion being induced in endometriosis by estrogens [171]. MIF stimulates endothelial cell proliferation, endometriotic lesion survival, expression of PGE2, COX-2, VEGF, IL-8, MCP-1, aromatase, and reciprocally stimulates TNF-a in endometrial cells [56,152,158,172]. ISO-1, MIF antagonist, is responsible for a significant reduction in endometriotic lesion size, in experimental models, by inhibiting cell adhesion, tissue remodeling, angiogenesis, and inflammation, in addition to alteration of the balance between pro-and anti-apoptotic factors [155].…”

Co-morbidity of type 1 diabetes and endometriosis: bringing a new paradigm into focus

“…By using non-obese diabetic mice, Lee et al (2005) demonstrated that TNF-α initiates T1DM autoimmunity by regulating the maturation of dendritic cells, leading to the activation of islet-specific pancreatic lymph node T-cells. Macrophage migration inhibitor factor-1 (MIF-1), another pro-inflammatory cytokine implicated in the innate immune system, showed significantly higher expression in EU of women with ENDO than in normal (control) endometrium, and its levels were highly upregulated by estrogen (Veillat et al 2012, Rakhila et al 2014. Expression of MIF's specific receptor CD74 is also higher in human EC, where it is postulated to contribute to epithelial cell survival and enhanced IL-8 expression (Nothnick et al 2018).…”

Macrophage – the Central Link of the Endometrial Tissue Communication System

“…В последующем было показано, что макрофаги способны влиять на МСК-Э и способствовать их дифференцировке по пути эпителиальных клеток будущих маточных желез [10]. Активно вырабатывая фактор, ингибирующий миграцию макрофагов (MIF), который обладает ангиогенным эффектом, макрофаги эндометрия являются ключевым звеном тканевого ремоделирования и восстановления данной ткани [42,12]. Стоит вспомнить, что противовоспалительная субпопуляция макрофагов (М2) участвует в процессе нейрогенеза [51] и способствует восстановлению иннервации ткани эндометрия.…”