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While bacteria often cause painful cutaneous reactions, host skin invasion by the human parasitic helminth Schistosoma mansoni often goes unnoticed. This study interrogated whether pain-sensing skin afferents marked by expression of the ion channel Transient Receptor Potential Vanilloid 1 (TRPV1) contributed to the detection and initiation of skin immunity against S. mansoni. Data show that percutaneous S. mansoni infection significantly reduced thermal pain sensitivity evoked by TRPV1+ neurons. Consistently, isolated skin sensory neurons from infected mice had significantly reduced calcium influx and neuropeptide release in response to the TRPV1 agonist capsaicin compared to neurons from na\u00efve controls. Using gain- and loss-of-function approaches to test whether TRPV1+ neurons initiate host-protective responses revealed that TRPV1+ neurons limit S. mansoni skin entry and migration into the pulmonary tract. Moreover, TRPV1+ neurons were both necessary and sufficient to promote proliferation and cytokine production from dermal \u03b3\u03b4 T cells and CD4+ T helper cells, as well as to enhance neutrophil and monocyte recruitment to the skin. Taken together, this work suggests that S. mansoni may have evolved to manipulate TRPV1+ neuron activation as a countermeasure to limit IL-17-mediated inflammation, facilitating systemic dissemination and chronic parasitism.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf141","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T20:07:57Z","timestamp":1755029277000},"page":"2700-2714","source":"Crossref","is-referenced-by-count":6,"title":["TRPV1+ neurons promote cutaneous immunity against\n                    <i>Schistosoma mansoni<\/i>"],"prefix":"10.1093","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1134-9139","authenticated-orcid":false,"given":"Juan M","family":"Inclan-Rico","sequence":"first","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA,","place":["United States"]},{"name":"Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Stephenson","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA,","place":["United States"]},{"name":"Department of Microbiology and Immunology, School of Medicine, Tulane University , New Orleans, LA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila M","family":"Napuri","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA,","place":["United States"]},{"name":"Department of Microbiology and Immunology, School of Medicine, Tulane University , New Orleans, LA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather L","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Yin","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1002-6138","authenticated-orcid":false,"given":"Christopher F","family":"Pastore","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqin","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA,","place":["United States"]},{"name":"Institute for Regenerative Medicine, School of Medicine, University of Pennsylvania , Philadelphia, PA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"De\u2019Broski R","family":"Herbert","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA,","place":["United States"]},{"name":"Department of Microbiology and Immunology, School of Medicine, Tulane University , New Orleans, LA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"2025103103530245900_vkaf141-B1","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1038\/nature12479","article-title":"Bacteria activate sensory neurons that modulate pain and 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