Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis
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 associat...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54486-6 |
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| author | 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 Francesco De Logu |
| author_facet | 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 Francesco De Logu |
| author_sort | Mustafa Titiz |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9ff86e38bb9f4084816ee6adaec03d94 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9ff86e38bb9f4084816ee6adaec03d942025-08-20T02:49:17ZengNature PortfolioNature Communications2041-17232024-11-0115111510.1038/s41467-024-54486-6Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosisMustafa Titiz0Lorenzo Landini1Daniel Souza Monteiro de Araujo2Matilde Marini3Viola Seravalli4Martina Chieca5Pasquale Pensieri6Marco Montini7Gaetano De Siena8Benedetta Pasquini9Silvia Vannuccini10Luigi Francesco Iannone11Thiago M. Cunha12Giulia Brancolini13Elisa Bellantoni14Irene Scuffi15Alessandra Mastricci16Martina Tesi17Mariarosaria Di Tommaso18Felice Petraglia19Pierangelo Geppetti20Romina Nassini21Francesco De Logu22Department of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Health Science, Obstetrics and Gynecology Section, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Experimental and Clinical Biomedical Sciences “Mario Serio”, Medical Genetics Unit, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Chemistry “U.Schiff”, University of FlorenceDepartment of Experimental and Clinical Biomedical Sciences, Obstetrics and Gynecology Unit, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirão Preto Medical School, University of São PauloFloNext srlDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Health Science, Obstetrics and Gynecology Section, University of FlorenceDepartment of Experimental and Clinical Biomedical Sciences, Obstetrics and Gynecology Unit, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceDepartment of Health Science, Clinical Pharmacology and Oncology Section, University of FlorenceAbstract 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.https://doi.org/10.1038/s41467-024-54486-6 |
| spellingShingle | 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 Francesco De Logu Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis Nature Communications |
| title | Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis |
| title_full | Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis |
| title_fullStr | Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis |
| title_full_unstemmed | Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis |
| title_short | Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis |
| title_sort | schwann cell c5ar1 co opts inflammasome nlrp1 to sustain pain in a mouse model of endometriosis |
| url | https://doi.org/10.1038/s41467-024-54486-6 |
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