The role of peripheral nerve signaling in endometriosis

Abstract

A hallmark of endometriosis - a chronic debilitating condition whose causes are poorly understood - is neuronal innervation of lesions. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with endometriosis but also contribute to a pro-growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. The diverse array of contributions that neurons play in endometriosis indicate that it should be considered as a nerve-centric disease. This review is focused on the emerging field of exoneural biology and how it applies to the field of endometriosis, in particular the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the mechanisms of neuronal contribution to endometriosis, as well as their interactions with accompanying stromal and immune cells, will unearth novel disease-relevant pathways and targets, providing additional, more selective therapeutic horizons.

Keywords: endometriosis; lesion; nerve signaling; nociceptor; peripheral nerves.

FIGURE 1

Overview of the broad and disparate symptoms associated with endometriosis. In endometriosis, lesion growth of endometrial tissue occurs outside of the endometrium. Lesions are composed of an abundance of distinct cell types including immune, stromal and epithelial cells as well as infiltrating blood vessels and nerves

FIGURE 2

Multifaceted role of estrogen in endometriosis: Estrogen can mediate the recruitment of immune cells, nerve fibers, and blood vessels to lesions. Macrophages and mast cells once recruited, contribute to neurite outgrowth and peripheral nerve sensitization, respectively. Estrogen strongly induces neurotrophin production, including NGF, BDNF, and NT‐3 by macrophages which signal through NTRK receptors on nerves to promote neurogenesis. Mast cell degranulation and the subsequent release of pro‐inflammatory mediators can be triggered by estrogen release. Release of pro‐inflammatory mediators from mast cells sensitizes peripheral nerve endings in endometriotic lesions, contributing to the pain. An estrogen‐dependent detrimental cycle of macrophage‐mediated neurogenesis and mast‐cell mediated inflammation and sensitization drives the pro‐growth cycle necessary for endometriosis progression. BDNF, Brain‐Derived Neurotropic Factor; NGF, Nerve Growth Factor; NGFR, Nerve Growth Factor Receptor; NT‐3, Neurotrophin‐3; NTRK, Neurotrophic Tyrosine Receptor Kinase

FIGURE 3

Schematic proposal for the inter‐dependent nature of estrogen, macrophages, and peripheral nerve fibers in driving endometriotic lesion growth. Peripheral nerves not only drive sensitization and pain associated with endometriosis but can also promote recruitment of macrophages to lesions, resulting in a pro‐growth inflammatory environment