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

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 e...

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Bibliographic Details
Published in:Nature communications Vol. 15; no. 1; pp. 10142 - 15
Main Authors: Titiz, Mustafa, Landini, Lorenzo, Souza Monteiro de Araujo, Daniel, Marini, Matilde, Seravalli, Viola, Chieca, Martina, Pensieri, Pasquale, Montini, Marco, De Siena, Gaetano, Pasquini, Benedetta, Vannuccini, Silvia, Iannone, Luigi Francesco, Cunha, Thiago M., Brancolini, Giulia, Bellantoni, Elisa, Scuffi, Irene, Mastricci, Alessandra, Tesi, Martina, Di Tommaso, Mariarosaria, Petraglia, Felice, Geppetti, Pierangelo, Nassini, Romina, De Logu, Francesco
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 25.11.2024
Nature Publishing Group
Nature Portfolio
Subjects:
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Adaptor Proteins, Signal Transducing
Animals
Apoptosis Regulatory Proteins - genetics
Apoptosis Regulatory Proteins - metabolism
Back pain
Cell activation
Chronic pain
Complement C5a - metabolism
Complement component C5a
Disease Models, Animal
Endometriosis
Endometriosis - metabolism
Endometriosis - pathology
Fatigue
Female
Fibromyalgia
Headache
Humanities and Social Sciences
Humans
IL-1β
Inflammasomes
Inflammasomes - metabolism
Interleukin-1beta - metabolism
Macrophages
Macrophages - metabolism
Mice
Mice, Inbred C57BL
Migraine
multidisciplinary
Nerves
Oxidative Stress
Pain
Pain - metabolism
Pain sensitivity
Receptor, Anaphylatoxin C5a - genetics
Receptor, Anaphylatoxin C5a - metabolism
Receptors
Schwann cells
Schwann Cells - metabolism
Science
Science (multidisciplinary)
Therapeutic targets
TRPA1 Cation Channel - genetics
TRPA1 Cation Channel - metabolism
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. Endometriosis affects over 60% of women, leading to widespread pain. Here, the authors show that blocking C5a receptor (C5aR1) in Schwann cells reduces pain by inhibiting pathways that trigger inflammation, oxidative stress, and nerve sensitivity, revealing a potential therapeutic target in endometriosis pain management.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-54486-6