Excessive epithelial mechanosensation drives nociceptive innervation and chronic bladder pain via the PIEZO1-SLC7A11-glutamate axis
Epithelial mechanosensation maintains tissue homeostasis by sensing mechanical stimuli. Dysregulated mechanotransduction has been implicated in chronic pain, yet the molecular link between epithelial stress and persistent sensory dysfunction remains unclear.
Here, we report that the mechanosensitive ion channel PIEZO1 is markedly upregulated in bladder epithelial cells under recurrent uropathogenic E. coli infection through interleukin-6 (IL-6)-dependent signaling. PIEZO1 overexpression amplifies mechanotransduction-induced reactive oxygen species (ROS) generation, triggering a homeostatic antioxidant response via the cystine-glutamate antiporter system Xc⁻ (SLC7A11).
This protective mechanism inadvertently promotes extracellular glutamate accumulation, driving aberrant sprouting and hyperinnervation of peptidergic nociceptive C fibers into the epithelial layer. This neuroepithelial remodeling sensitizes bladder afferents and induces persistent pain-like states resembling chronic visceral pain and organ dysfunction.
Our findings reveal a paradoxical role of epithelial antioxidant defense in promoting pain through the PIEZO1-SLC7A11-glutamate axis and highlight the neuroepithelial interface as a key therapeutic target for infection-induced chronic pain syndromes.
HIGHLIGHTS
• IL-6 upregulates epithelial PIEZO1 to amplify pathological mechanotransduction
• PIEZO1-driven Ca2+ influx induces NRF2-SLC7A11 antioxidant signaling
• SLC7A11-mediated glutamate release drives nociceptive C-fiber hyperinnervation
• Neuroepithelial remodeling underlies persistent bladder pain and voiding dysfunction
Web | DOI | PDF | Cell | Open Access
Min Jung Kim; Joo Hwan Noh; Ho Young Lee; Bohm Lee; Alexander Doh Park; Hyeonseo Oh; Geun-Woo D Kim; Hye-Sook Lee; Yeonsoo Oh; Hyeonje Hwang; Chungoo Kim; Hyeonjong Lee; Xue Li; Mi Mi Oh; Donghoon Lim; Soman N Abraham; Yongcheol Cho; Sung Wook Chi; Hae Woong Choi
Epithelial mechanosensation maintains tissue homeostasis by sensing mechanical stimuli. Dysregulated mechanotransduction has been implicated in chronic pain, yet the molecular link between epithelial stress and persistent sensory dysfunction remains unclear.
Here, we report that the mechanosensitive ion channel PIEZO1 is markedly upregulated in bladder epithelial cells under recurrent uropathogenic E. coli infection through interleukin-6 (IL-6)-dependent signaling. PIEZO1 overexpression amplifies mechanotransduction-induced reactive oxygen species (ROS) generation, triggering a homeostatic antioxidant response via the cystine-glutamate antiporter system Xc⁻ (SLC7A11).
This protective mechanism inadvertently promotes extracellular glutamate accumulation, driving aberrant sprouting and hyperinnervation of peptidergic nociceptive C fibers into the epithelial layer. This neuroepithelial remodeling sensitizes bladder afferents and induces persistent pain-like states resembling chronic visceral pain and organ dysfunction.
Our findings reveal a paradoxical role of epithelial antioxidant defense in promoting pain through the PIEZO1-SLC7A11-glutamate axis and highlight the neuroepithelial interface as a key therapeutic target for infection-induced chronic pain syndromes.
HIGHLIGHTS
• IL-6 upregulates epithelial PIEZO1 to amplify pathological mechanotransduction
• PIEZO1-driven Ca2+ influx induces NRF2-SLC7A11 antioxidant signaling
• SLC7A11-mediated glutamate release drives nociceptive C-fiber hyperinnervation
• Neuroepithelial remodeling underlies persistent bladder pain and voiding dysfunction
Web | DOI | PDF | Cell | Open Access