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More recently, these specialized cells have emerged as key contributors to mucosal immunity, orchestrating immune activation. Epididymitis is an inflammatory condition that significantly impacts male fertility, often due to a lack of diagnosis and treatment. This study investigates the role of region-specific epididymal proton-secreting clear cells (CCs) in shaping immune responses during LPS-induced epididymitis in mice. We found that in response to lipopolysaccharide (LPS), CCs rapidly shifted to a proinflammatory phenotype, marked by the upregulation of cytokines and chemokines, alongside the downregulation of genes involved in sperm maturation. Morphological changes in CCs, including increased apical blebs and altered shape across different epididymal segments, suggest their active role in immune responses. Moreover, mononuclear phagocytes reduced their luminal-reaching projections in the proximal epididymis after the LPS challenge. This bacterial antigen triggered dendritic cell migration and neutrophil infiltration in the distal epididymis. These immune landscape alterations contributed to epithelial damage and impaired sperm maturation, as evidenced by decreased sperm motility following LPS intravasal-epididymal injection. Our findings indicate that proton-secreting cells are immune gatekeepers in the epididymis, initiating immune responses and disrupting sperm maturation. This research enhances the understanding of epithelial immunoregulation and will help to develop novel diagnostic and therapeutic strategies for epididymitis and male infertility. Furthermore, insights into CC-mediated immune responses could inform the development of new approaches for male contraception.<\/jats:p>","DOI":"10.1093\/function\/zqaf023","type":"journal-article","created":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T07:35:20Z","timestamp":1748763320000},"source":"Crossref","is-referenced-by-count":7,"title":["Proton-Secreting Cells as Drivers of Inflammation and Sperm Dysfunction in LPS-Induced Epididymitis"],"prefix":"10.1152","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7729-2115","authenticated-orcid":false,"given":"A A S","family":"Da\u00a0Silva","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School Program in Membrane Biology, Nephrology Division, Department of Medicine, , Boston, MA 02129 ,","place":["USA"]},{"name":"Federal University of S\u00e3o Paulo Department of Morphology and Genetics, , S\u00e3o Paulo, 04039-001 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