Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis

Mustafa Titiz, Lorenzo Landini, Daniel Souza Monteiro de Araujo, Matilde Marini, Viola Seravalli, Martina Chieca, Pasquale Pensieri, Marco Montini, Gaetano De Siena, Benedetta Pasquini, Silvia Vannuccini, Luigi Francesco Iannone, Thiago M. Cunha, Giulia Brancolini, Elisa Bellantoni, Irene Scuffi, Alessandra Mastricci, Martina Tesi, Mariarosaria Di Tommaso, Felice Petraglia, Pierangelo Geppetti, Romina Nassini () and Francesco De Logu ()
Additional contact information
Mustafa Titiz: University of Florence
Lorenzo Landini: University of Florence
Daniel Souza Monteiro de Araujo: University of Florence
Matilde Marini: University of Florence
Viola Seravalli: University of Florence
Martina Chieca: University of Florence
Pasquale Pensieri: University of Florence
Marco Montini: University of Florence
Gaetano De Siena: University of Florence
Benedetta Pasquini: University of Florence
Silvia Vannuccini: University of Florence
Luigi Francesco Iannone: University of Florence
Thiago M. Cunha: University of São Paulo
Giulia Brancolini: FloNext srl
Elisa Bellantoni: University of Florence
Irene Scuffi: University of Florence
Alessandra Mastricci: University of Florence
Martina Tesi: University of Florence
Mariarosaria Di Tommaso: University of Florence
Felice Petraglia: University of Florence
Pierangelo Geppetti: University of Florence
Romina Nassini: University of Florence
Francesco De Logu: University of Florence

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Over 60% of women with endometriosis experience abdominopelvic pain and broader pain manifestations, including chronic back pain, fibromyalgia, chronic fatigue, vulvodynia, and migraine. Although the imbalance of proinflammatory mediators, including the complement component C5a, is associated with endometriosis-related pain, the mechanisms causing widespread pain and the C5a role remain unclear. Female mice and women with endometriosis exhibit increased plasma C5a levels and pain. We hypothesize the Schwann cells involvement in endometriotic pain. Here, we show that silencing the C5a receptor (C5aR1) in Schwann cells blocks the C5a-induced activation of the NLRP1 inflammasome and subsequent release of interleukin-1β (IL-1β). Macrophages, recruited to sciatic/trigeminal nerves by IL-1β from Schwann cells, increase oxidative stress, which activates the proalgesic TRPA1 pathway, resulting in widespread pain. These findings reveal a pathway involving Schwann cell C5aR1, NLRP1/IL-1β activation, macrophage recruitment, oxidative stress, and TRPA1 engagement, contributing to pain in a mouse model of endometriosis.

Date: 2024
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DOI: 10.1038/s41467-024-54486-6

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