Immune-Regulatory Molecule CD69 Controls Peritoneal Fibrosis.

Abstract

Patients with ESRD undergoing peritoneal dialysis develop progressive peritoneal fibrosis, which may lead to technique failure. Recent data point to Th17-mediated inflammation as a key contributor in peritoneal damage. The leukocyte antigen CD69 modulates the setting and progression of autoimmune and inflammatory diseases by controlling the balance between Th17 and regulatory T cells (Tregs). However, the relevance of CD69 in tissue fibrosis remains largely unknown. Thus, we explored the role of CD69 in fibroproliferative responses using a mouse model of peritoneal fibrosis induced by dialysis fluid exposure under either normal or uremic status. We found that cd69^-/- mice compared with wild-type (WT) mice showed enhanced fibrosis, mesothelial to mesenchymal transition, IL-17 production, and Th17 cell infiltration in response to dialysis fluid treatment. Uremia contributed partially to peritoneal inflammatory and fibrotic responses. Additionally, antibody-mediated CD69 blockade in WT mice mimicked the fibrotic response of cd69^-/- mice. Finally, IL-17 blockade in cd69^-/- mice decreased peritoneal fibrosis to the WT levels, and mixed bone marrow from cd69^-/- and Rag2^-/-_γc^-/- mice transplanted into WT mice reproduced the severity of the response to dialysis fluid observed in cd69^-/- mice, showing that CD69 exerts its regulatory function within the lymphocyte compartment. Overall, our results indicate that CD69 controls tissue fibrosis by regulating Th17-mediated inflammation.