**1. Introduction**

Endometriosis (EM) is an estrogen-dependent benign, chronic inflammatory disease affecting up to 10 to 15% of reproductive-aged women [1–3]. It is associated with a significant societal and economic burden that costs the US economy USD 22 billion annually in lost productivity and direct healthcare costs [3–6]. The main symptoms of EM include dysmenorrhea, dyspareunia, dyschezia, dysuria, noncyclic chronic pelvic pain, and primary or secondary fertility problems [7–9].

EM is a disease of the uterine tissues (epithelium, stroma, and smooth muscle cells) that leads to ectopic colonization by detachment/desquamation of basal endometrial stem cells during menstruation or by infiltration into the myometrium [10–12]. Even if the pathogenesis is unclear, over the last 20 years, our understanding of the mechanisms driving EM lesion growth and pain presentation has evolved (Figure 1). Significant advances have been made in understanding how estrogen drives tissue pathology, resulting in aberrant inflammatory and neuronal states, and promoting the invasion of lesions into the surrounding tissues [13].

In this review, we summarize the role of neurogenic inflammation in endometriotic pain. A better understanding of the role of the peripheral nerve system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.

**Citation:** Velho, R.V.; Taube, E.; Sehouli, J.; Mechsner, S. Neurogenic Inflammation in the Context of Endometriosis—What Do We Know? *Int. J. Mol. Sci.* **2021**, *22*, 13102. https://doi.org/10.3390/ijms222313102

Academic Editors: Antonio Simone Laganà and Kanako Hayashi

Received: 20 October 2021 Accepted: 1 December 2021 Published: 3 December 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**Figure 1.** Main pathways involved in the pathogenesis of inflammatory pain in endometriosis. Endometrial fragments in the peritoneum lead to peritoneal inflammation. The same immune response is seen at endometriotic lesions, where the increased production of cytokines, chemokines, growth factors and immune cells also contributes to an enhanced inflammatory environment present in the peritoneal cavity of women with EM. Of these inflammatory mediators, PGE2, tumour necrosis factor-α (TNFα), nerve growth factor (NGF), RANTES and interleukins are also able to stimulate sensory nerve endings and activate a positive feedback loop, further increasing proinflammatory modulator production. The expression of pain receptors is also increased in EM patients' nerve fibres. The enhanced stimulation and activation of peripheral nerve endings in the peritoneal cavity increase the painful stimuli, initiating and maintaining chronic pelvic pain.
