Macrophage migration inhibitory factor is involved in ectopic endometrial tissue growth and peritoneal-endometrial tissue interaction in vivo: a plausible link to endometriosis development.

Halima Rakhila,Mathieu Leboeuf,Ali Akoum,Madeleine Lemyre,Karine Girard,Benedetta Bussolati

doi:10.1371/journal.pone.0110434

Halima Rakhila, Mathieu Leboeuf + Show 4 more

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https://doi.org/10.1371/journal.pone.0110434

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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.

Highlights

Endometriosis is an estrogen-dependent inflammatory disease defined by the presence of endometrial glands and stroma outside the uterine cavity
Using a migration inhibitory factor (MIF)-knock out (KO) model and a control wild type (WT) mouse model of endometriosis, where syngeneic endometrial tissue was injected into the peritoneal cavity and allowed to implant and grow, our data first showed that MIF absence markedly reduced endometrial tissue growth into the peritoneal host tissue and resulted in a significant diminution of the number and size of endometrial implants
Selective inhibition of MIF using a specific inhibitor (ISO-1) in WT mice led to comparable outcomes, whereas MIFadd back to MIF-KO animals significantly increased endometriosis-like lesions’ size and number

Summary

Introduction

Endometriosis is an estrogen-dependent inflammatory disease defined by the presence of endometrial glands and stroma outside the uterine cavity. A variety of genetic, hormonal, immune and inherent endometrial changes may support the development of endometriosis lesions within the peritoneum of affected women and the progression of the disease. The available literature points to an important role for macrophage migration inhibitory factor (MIF). Beyond its eponymous effect on activating or inhibiting macrophage mobility, MIF is understood as a major pro-inflammatory factor and a critical upstream regulator of innate immunity [5,6]. Studies with MIF-deficient mice confirmed an upstream activating role for MIF in diverse inflammatory responses in the host response to infection and tumorigenesis [7,8]. In addition to directly inducing angiogenesis, MIF helps, thereby increasing the release of other growth and angiogenic factors [9,10,11,12,13]

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