Repeatedly occurring retrograde menstruation intensifies central sensitization driven by neuroinflammation in endometriosis models
Madeleine E. Harvey, Mingxin Shi, Yeongseok Oh, Taylor M. Page, Debra A. Mitchell, Addie Luo, Ov D. Slayden, James A. MacLean, Anjali Sharma, Kanako Hayashi
Madeleine E. Harvey, Mingxin Shi, Yeongseok Oh, Taylor M. Page, Debra A. Mitchell, Addie Luo, Ov D. Slayden, James A. MacLean, Anjali Sharma, Kanako Hayashi
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Research Article Inflammation Reproductive biology

Repeatedly occurring retrograde menstruation intensifies central sensitization driven by neuroinflammation in endometriosis models

Abstract

This study investigated how chronic pelvic pain (CPP) develops using rhesus macaques with naturally occurring endometriosis and a multiple lesion induction mouse model (MIM), as repeated retrograde menstruation is considered an underlying mechanism of endometriosis pathogenesis. MIM increased lesion numbers and elevated hypersensitivity. Elevated persistent glial cell activation was observed across multiple brain regions or spinal cords in MIM and rhesus macaques. Elevated TRPV1, SP, and CGRP expressions in the dorsal root ganglia (DRG) were persistent in MIM. MIM induced the severe disappearance of TIM4hiMHCIIlo residential macrophages and an influx of increased pro-inflammatory TIM4loMHCIIhi macrophages in the peritoneal cavity. Cytokine levels were persistently elevated in MIM. Furthermore, dienogest (a synthetic progestin) and fingolimod (a selective immunosuppressor) reduced hyperalgesia and neuroinflammation. Our results indicate that recurrent retrograde menstruation can be a peripheral stimulus that induces nociceptive pain and creates a composite chronic inflammatory stimulus, leading to neuroinflammation and sensitization of the central nervous system. The circuits of neuroplasticity and stimulation of peripheral organs via a feedback loop of neuroinflammation may mediate widespread endometriosis-associated CPP. These findings in mice were further supported by results from the spontaneously developed advanced endometriosis in rhesus macaques via recurrent retrograde menstruation.

Authors

Madeleine E. Harvey, Mingxin Shi, Yeongseok Oh, Taylor M. Page, Debra A. Mitchell, Addie Luo, Ov D. Slayden, James A. MacLean, Anjali Sharma, Kanako Hayashi

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Figure 14

Multiple lesion induction increased chronic inflammation and neuroinflammation, enhancing endometriosis-associated CPP.

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Multiple lesion induction increased chronic inflammation and neuroinflam...
Created by Biorender. Multiple inductions enhance peripheral sensitization via peripheral chronic inflammation and altered peritoneal macrophage profiles (circle 1). Peripheral inflammation sensitizes nociceptor neurons in endometriotic lesions and/or in pelvic organs, as well as sensory neurons in the DRG (circle 2). The stimuli further sensitize the CNS (circle 3), leading to chronic endometriosis-associated CPP (circle 4). Multiple inductions of lesions induce persistent glial and astrocyte activation as a sign of neuroinflammation across several brain regions (circle 5) linked to pain processing, anxiety, depression, and stress response (circle 6). Dienogest and fingolimod reduce neuroinflammation and hyperalgesia in our multiple-induction endometriosis model, indicating that neuroinflammation drives endometriosis-associated CPP via central sensitization. While chronic systemic or peripheral inflammatory factors and altered immune cells can disrupt the BBB, promoting glial and astrocyte activation, the mechanisms by which peripheral inflammation drives endometriosis-associated neuroinflammation remain to be studied (circle 7). Neuroinflammation can give feedback to stimulate peripheral organs, potentially inducing widespread pain in patients with endometriosis (circle 8). Thus, recurrent retrograde menstruation can be a peripheral stimulus that induces nociceptive pain and triggers a composite chronic inflammatory response, which may be crucial in causing neuroinflammation and further sensitizing the CNS. The circuits of neuroplasticity, driven by chronic inflammation and peripheral organ stimulation via the neuroinflammation feedback loop, may induce widespread endometriosis-associated CPP.