Biology subjects

Avenatti, M. C.

Publications and source records attributed to Avenatti, M. C..

3 recordsLinked to original sources

bioRxiv2025

Immunomodulatory Functions of Intercalated Cells in Kidney Autoimmunity

Various autoimmune diseases frequently cause both acute and chronic kidney injuries through complex mechanisms involving autoantibodies and cellular immune responses that result in tissue damage. Intercalated cells (ICs), specialized renal tubular epithelial cells responsible for proton secretion, are strategically positioned at the epithelial-immune interface, making them ideal sensors of stress signals and potential triggers of immune responses. This study investigates the molecular mechanisms by which ICs interact with immune cells to maintain renal immune homeostasis and contribute to the development of autoimmune kidney disease. We depleted Foxp3 regulatory T cells (Tregs) by injecting diphtheria toxin (DT) into male and female Foxp3-DTR mice. Two weeks after depletion, we observed autoimmune inflammation marked by increased renal immune infiltration, including neutrophils, macrophages, and subsets of T and B cells, along with the formation of ectopic lymphoid-like structures and enhanced antigen presentation. We found higher levels of renal autoantibodies in urine and serum, with antibodies depositing in glomeruli and tubules. Our analysis identified several renal antigens targeted by autoantibodies, suggesting their potential role in antibody-mediated renal injury. Kidney damage included smaller glomeruli, proximal tubular injury, an increased urine albumin/creatinine ratio, and decreased urine output. Disruption of immune tolerance led to the upregulation of inflammasome-related genes and IL-33 in ICs, which acts as a key alarmin signaling damage and promoting activation and expansion of Tregs. Our findings uncover a novel IC-Treg interaction mediated by the IL-33 pathway, revealing immune-regulating mechanisms that support renal immune tolerance. Although Tregs were initially depleted, a significant rebound in their numbers and function occurred. Understanding the cellular and molecular mechanisms behind autoimmune renal injury is crucial for developing targeted therapies and identifying appropriate biomarkers.

immunology↗

bioRxiv2025

Proton-secreting cells modulate mucosal immune surveillance in the male reproductive tract

Proton-secreting cells in various organs, such as the kidney and epididymis, regulate pH balance, maintaining cellular homeostasis, and supporting key physiological processes. 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 explores the involvement of region-specific epididymal proton-secreting clear cells (CCs) in the immune response by interacting with the immune system during LPS-induced mouse epididymitis. We found that in response to 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 (MPs) reduced their luminal-reaching projections in the proximal epididymis after the LPS challenge. This bacteria antigen triggered the migration of dendritic cells 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 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.

developmental biology↗

bioRxiv2024

Chronic inflammation drives epididymal tertiary lymphoid structure formation and autoimmune fertility disorders

The incomplete understanding of epididymal mucosal immunity is a significant contributing factor to the classification of many male infertility cases as idiopathic. Conditions that disrupt the immune balance in the male reproductive tract, such as vasectomy and infections, can expose sperm to the immune system, leading to increased production of anti-sperm antibodies (ASAs) and subsequent reproductive challenges. Regulatory T cells (Tregs) regulate inflammation and maintain sperm tolerance. In a murine model, we demonstrated that disrupting sperm immunotolerance induces chronic autoimmune responses characterized by antibody production targeting sperm and reproductive tissue autoantigens and unique tissue-specific immune cell signatures in the epididymis and testis. Such inflammatory features impair sperm function, contribute to epididymal damage, and drive sustained male subfertility. Tertiary lymphoid structures (TLSs) were formed within the epididymis after Treg depletion, defined by clusters of heterogenous B and T cells, fibroblasts, and endothelial cells. These ectopic structures perpetuate inflammation and lower the activation threshold for future immune threats. Similar isotypes of autoantibodies were detected in the seminal plasma of infertile patients, suggesting shared mechanistic pathways between mice and humans. Overall, we provide an in-depth understanding of the diverse B- and T-cell dynamics and TLS formation during epididymitis to develop precision-targeted therapies for infertility and chronic inflammation. Additionally, this immunological characterization of the epididymal microenvironment has the potential to identify novel targets for the development of male contraceptives. One Sentence SummaryUnderstanding the epididymal immune cell landscape dynamics aids in developing targeted therapies for infertility and contraception.

immunology↗