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- Title
Recurrent infections drive persistent bladder dysfunction and pain via sensory nerve sprouting and mast cell activity.
- Authors
Hayes, Byron W.; Choi, Hae Woong; Rathore, Abhay P.S.; Bao, Chunjing; Shi, Jianling; Huh, Yul; Kim, Michael W.; Mencarelli, Andrea; Bist, Pradeep; Ng, Lai Guan; Shi, Changming; Nho, Joo Hwan; Kim, Aram; Yoon, Hana; Lim, Donghoon; Hannan, Johanna L.; Purves, J. Todd; Hughes Jr., Francis M.; Ji, Ru-Rong; Abraham, Soman N.
- Abstract
Urinary tract infections (UTIs) account for almost 25% of infections in women. Many are recurrent (rUTI), with patients frequently experiencing chronic pelvic pain and urinary frequency despite clearance of bacteriuria after antibiotics. To elucidate the basis for these bacteria-independent bladder symptoms, we examined the bladders of patients with rUTI. We noticed a notable increase in neuropeptide content in the lamina propria and indications of enhanced nociceptive activity. In mice subjected to rUTI, we observed sensory nerve sprouting that was associated with nerve growth factor (NGF) produced by recruited monocytes and tissue-resident mast cells. Treatment of rUTI mice with an NGF-neutralizing antibody prevented sprouting and alleviated pelvic sensitivity, whereas instillation of native NGF into naïve mice bladders mimicked nerve sprouting and pain behavior. Nerve activation, pain, and urinary frequency were each linked to the presence of proximal mast cells, because mast cell deficiency or treatment with antagonists against receptors of several direct or indirect mast cell products was each effective therapeutically. Thus, our findings suggest that NGF-driven sensory sprouting in the bladder coupled with chronic mast cell activation represents an underlying mechanism driving bacteria-independent pain and voiding defects experienced by patients with rUTI. Editor's summary: Recurrent urinary tract infections (rUTIs) are associated with urinary frequency and chronic pelvic pain, even in the absence of bacteria. Hayes et al. examined mechanisms of rUTI and observed that patient rUTI bladder biopsies had an increase in the neuropeptide substance P (SP) in the lamina propria (layer of bladder made of connective tissue and has blood vessels, nerves, and glands), which indicated an increase in nociceptive sensory nerves (involvedin pain sensing in peripheral tissues like the skin and genito-urinary tract). In a mouse model of rUTIs, bladders showed striking sensory nerve sprouting that was linked to elevated nerve growth factor (NGF) from monocytes and mast cells. NGF was also associated with increased pain and urinary frequency. These findings provide new insights into lingering rUTI symptoms. —Christiana Fogg
- Subjects
URINARY tract infections; MAST cells; BLADDER diseases; DISEASE relapse; NERVE growth factor; GERMINATION
- Publication
Science Immunology, 2024, Vol 9, Issue 93, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.adi5578