Macrophage and nerve interaction in endometriosis

Abstract

Dysregulation of the immune system in endometriotic milieus has been considered to play a pivotal role in the pathogenesis of endometriosis. Macrophage recruitment and nerve fiber infiltration are the two major characteristics of this aberrant immune environment. First, the recruitment of macrophages and their polarization phenotype within the endometriotic lesion have been demonstrated to facilitate the development and maintenance of endometriosis. M1 phenotype of macrophages has the capacity to secrete multiple cytokines for inflammatory response, while M2 macrophage possesses an opposite property that can mediate the process of immunosuppression and neuroangiogenesis. Upon secretion of multiple abnormal signal molecules by the endometriotic lesion, macrophages could alter their location and phenotype. These changes facilitate the accommodation of the aberrant microenvironment and the exacerbation of disease progression. Second, the infiltration of nerve fibers and their abnormal distribution are proved to be involved in the generation of endometriosis-associated pain and inflammatory response. An imbalance in sensory and sympathetic innervation and the abnormal secretion of different cytokines could mediate neurogenesis and subsequent peripheral neuroinflammation in endometriosis. Although endometriosis creates an inflammatory milieu promoting macrophage infiltration and an imbalanced innervation, interaction between macrophages and nerve fibers in this process remains unknown. The aim of this review is to highlight the role of macrophage and nerve interaction in endometriosis, where macrophage recruitment and neurogenesis can be the underlying mechanism of neuroinflammation and pathogenesis of endometriosis.

P2X3 receptor involvement in endometriosis pain via ERK signaling pathway

“…Endometriosis pain is thought to be a kind of inflammatory, nociceptive and neuropathic pain [ 17 , 39 ]. Herein we make a hypothesis that inflammatory mediators may activate nociceptive receptor P2X3 on the afferent neurons, leading to the sensitization of sensory neurons, and thus triggering endometriosis pain.…”

“…Herein we make a hypothesis that inflammatory mediators may activate nociceptive receptor P2X3 on the afferent neurons, leading to the sensitization of sensory neurons, and thus triggering endometriosis pain. It lies in: 1) An imbalance of innervation and the abnormal secretion of different cytokines could mediate neurogenesis and subsequent peripheral neuroinflammation in endometriosis [ 39 ]; 2) In the present study, it has been proved that P2X3 is expressed not only on endometrial epithelial cells but also endometrial stromal cells and CGRP-positive nerve fibers within endometriotic lesions; 3) As ligand of receptor of P2X3, ATP, which is a neurotransmitter and pain factor, will increase in pathological conditions, including inflammation, stress, injury and tension [ 40 ]; 4) Endometriosis is considered as a kind of inflammatory and/or neuropathic disease [ 39 , 41 ]; 5) In theory, microcavities exist in endometriotic lesion and its tension fluctuates with the menstruation; 6) ATP releasing from epithelium lining the tube or sac acts on P2X3 and/or P2X2/3 receptors on subepithelial sensory nerves to convey sensory/nociceptive information to the central nervous system [ 40 ].…”

Microbiome of the Lower Genital Tract in Chinese Women with Endometriosis by 16s rRNA Sequencing Technique: A Pilot Study

“…1f), merely metabolism/lipid metabolism/synthesis and degradation of ketone bodies was identified, and this was significantly higher in the EM group than in the AM group. the uterine cavity [8,16]. Some researchers have successfully proven the non-sterilized environment through 16s-rRNA sequencing [17] and bacterial culture [16] methods.…”

Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis

“…In this process, diverse growth and pro-angiogenic factors play important roles, such as vascular endothelial growth factor (VEGF) that is regulated by E2 and responds to an inflammatory microenvironment, promoting endothelial cell proliferation (37,38). Neurogenesis is linked to both inflammatory response and angiogenesis and, along with an imbalance in sensory and sympathetic innervation, contributes to the growth of nerve fibers, subsequent peripheral neuroinflammation, and generation of chronic pain (39). One of the postulated consequences of immune cell activation in the endometriosis microenvironment is the production of cytokines, growth factors, and eicosanoids that simultaneously stimulate lesion innervation and neovascularization through a coordinated mechanism that is known as neuroangiogenesis (40).…”