Villainous role of estrogen in macrophage-nerve interaction in endometriosis

Abstract

Endometriosis is a complex and heterogeneous disorder with unknown etiology. Dysregulation of macrophages and innervation are important factors influencing the pathogenesis of endometriosis-associated pain. It is known to be an estrogen-dependent disease, estrogen can promote secretion of chemokines from peripheral nerves, enhancing the recruitment and polarization of macrophages in endometriotic tissue. Macrophages have a role in the expression of multiple nerve growth factors (NGF), which mediates the imbalance of neurogenesis in an estrogen-dependent manner. Under the influence of estrogen, co-existence of macrophages and nerves induces an innovative neuro-immune communication. Persistent stimulation by inflammatory cytokines from macrophages on nociceptors of peripheral nerves aggravates neuroinflammation through the release of inflammatory neurotransmitters. This neuro-immune interaction regulated by estrogen sensitizes peripheral nerves, leading to neuropathic pain in endometriosis. The aim of this review is to highlight the significance of estrogen in the interaction between macrophages and nerve fibers, and to suggest a potentially valuable therapeutic target for endometriosis-associated pain.

Keywords: Endometriosis; Estrogen; Macrophage; Nerve fiber; Neuroinflammation.

Fig. 1

Recruitment of macrophages by nerve fibers in an estrogen-dependent manner. Upon the influence of estrogen, nerve fibers can secrete LIF, IL1 and PAP3, mediating the recruitment of macrophages. Estrogen can enhance the release of CSF1 and CCL2 to promote migration of macrophages toward peripheral nerves. The interaction of CCL2 and its receptors activates the polarization of macrophages. Synergistic effect of estrogen and TCDD can also induce the M2 polarization of macrophages through activation of the STAT3 and P38-MAPK pathway. LIF: leukemia inhibitory factor; IL1: interleukin 1; PAP3: pancreatitis- associated protein 3; CSF1: colony-stimulating factor 1; CCL2: C-C motif ligand 2; CCR: C-C motif chemokine receptor; TCDD: 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin; ER: estrogen receptor

Fig. 2

Neurogenesis regulated by macrophages in an estrogen-dependent manner. Estrogen can upregulate the expression of NGF from macrophages through the induction of c-Fos/c-Jun heterodimers. Expression of NT3 and BDNF is also increased in response to estrogen. Both of their receptors, TrkB and p75NTR, are upregulated under the effect of estrogen on peripheral nerves. The expression of Sema3F and Sema3C from macrophage can reduce the sympathetic innervation through binding their receptors, NRP1 and NRP2. High level of HGF from macrophage induces the expression of Sema3A from myoblast in response to estrogen. Estrogen can also stimulate the secretion of VEGF from macrophage and increase the expression of the VEGF receptor flk on peripheral nerve. Imbalanced concentration of VEGF and Sema3A can activate the nerve fiber via NRP1-VEGFR2 axis. Dysregulation of all nerve growth factors from macrophage and their receptors on nerve fibers eventually result in aberrant neurogenesis in endometriosis. NGF: nerve growth factor; NT3: neurotrophin 3; BDNF: brain-derived nerve growth factor; TrkB: tyrosine kinase receptor B; Sema3F, 3C, 3A: Semaphorin 3F, 3C, 3A; NRP1, 2: neuropilin1, 2; HGF: hepatocyte growth factor; VEGF: vascular epithelial growth factor; flk: vascular epithelial growth factor receptor 2

Fig. 3

Role of estrogen in inflammation in endometriosis. Estrogen not only stimulates the secretion of inflammatory cytokines from macrophages, but also upregulate the expression of nociceptors on nerve fibers. IL1β, MCP1 and TNFα from macrophage can activate TRPA1 and TRPV1 on peripheral nerves. NGF from macrophages can also activate TRPV1, resulting in cross-sensitization of the TRPA1 and TRPV1 receptors. The interaction of MCP1 and its receptor Na.V sensitizes nerve fiber through a CCR/Gβγ-dependent mechanism. Macrophage-derived ATP stimulates the action of nerve fiber via P2X purinoreceptor. Persistent stimulation of peripheral nerve can promote the secretion of inflammatory neurotransmitters from nerve fibers. Expression of SP and CGRP can be modulated by estrogen. Release of SP from nerve fibers activates its receptor NK1R on macrophages in response to estrogen, resulting in up-regulation of CXCL8 and IL1β form macrophage. The activity of SP and CGRP can also alter the polarization of macrophage toward M2 phenotype. Macrophage-derived inflammation and neurogenic inflammation are both regulated by estrogen inducing a vicious circle to aggravate peripheral sensitization MCP1: monocyte chemoattractant protein 1; TNFα: tumor necrosis factor α; TRPA1: transient receptor potential cation channel, subfamily A, member 1; TRPV1: transient receptor potential vanilloid 1; SP: substance P; CGRP: calcitonin gene-related peptide; NK1R: neurokinin 1 receptor; CXCL8: chemokine (C-X-C motif) ligand 8.

Fig. 4

Significance of estrogen in endometriosis. Dysregulation of estrogen in endometriosis can mediate multiple aspects in endometriosis, including recruitment and polarization of macrophages, neurogenesis and angiogenesis. The interaction of macrophages and nerve fibers regulated by estrogen establish a vicious circle, aggravating inflammation in endometriotic milieu. Persistent inflammatory stimulation on peripheral nerve fiber result in peripheral sensitization, therefore exacerbating the progression of endometriosis