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Papers of the Week

Papers: 6 May 2023 - 12 May 2023

Basic Science

Human Studies, Molecular/Cellular, Neurobiology

Abdominal/Pelvic Pain, Inflammation/Inflammatory

2023 May 08

Am J Pathol


Neurotrophins and their receptors, novel therapeutic targets for pelvic pain in endometriosis, are coordinately regulated by interleukin-1β via the JNK signaling pathway.


Yu J, Berga SL, Zou E, Schrepf AD, Clauw DJ, As-Sanie S, Taylor RN


Pelvic pain in women with endometriosis is attributed to neuroinflammation and afferent nociceptor nerves in ectopic and eutopic endometrium. The hypothesis that uterine nociception is activated by IL-1β, a prominent cytokine in endometriosis, which induces expression of endometrial neurotrophins and their cognate receptors in vitro was tested. Immunofluorescence histochemistry confirmed the presence of neurons in human endometrial tissue. Expression of NGF and BDNF and their receptors in endometrial tissue and cells was validated by immunohistochemistry and Western blotting. Isolated endometrial stromal cells (ESC) were subjected to dose-response and time-course experiments with IL-1β and kinase inhibitors used to characterize in vitro biomarkers. Neural biomarkers were co-localized in endometrial nerve fibers. NGF, BDNF and their receptors TrkA, TrkB and p75 NTR were all expressed in primary ESC. IL-1β stimulated higher TrkA/B expression in ESC derived from endometriosis cases (2.8 ± 0.2-fold) than cells from control subjects (1.5 ± 0.3-fold, t-test, P<0.01); effects that were mediated via the c-Jun N-terminal Kinase (JNK) pathway. BDNF concentrations trended higher in peritoneal fluid of endometriosis cases but were not statistically different from controls (P=0.16). The results support the hypothesis that NGF and BDNF and their corresponding receptors orchestrate innervation of the endometrium, which is augmented by IL-1β. We postulate that JNK inhibitors, like SP600125, may have the potential to reduce neuroinflammation in women with endometriosis.