Rab27 a regulates dendritic cell immune tolerogenic capacity

Background Dendritic cells (DCs) serve as pivotal modulators of immune tolerance, with interleukin-10 (IL-10) secretion acting as a core mechanism to sustain this regulatory function. Rab27a, a small GTPase involved in vesicular trafficking processes, is well recognized for its critical role in cellular secretion events. However, its specific function in governing IL-10 release from DCs remains unclarified. This study aimed to decipher the molecular mechanisms through which Rab27a regulates IL-10 secretion in DCs and explore the relevance of this pathway to immune dysregulation in food allergy (FA). Methods Bone marrow-derived dendritic cells (BMDCs) were isolated from C57BL/6 mice and purified using flow cytometry. Plasmacytoid DCs (pDCs) were obtained from the peripheral blood of FA patients and age-matched healthy control individuals for comparative analysis. Results Peripheral pDCs from FA patients exhibited notably reduced Rab27a activation levels compared to those from healthy controls. Concurrently, DCs from FA patients showed impaired immune tolerogenic function, as evidenced by their decreased ability to induce type 1 regulatory T (Tr1) cells. A strong positive correlation was observed between Rab27a activation and the induction of Tr1 cells by DCs. Mechanistically, activated Rab27a formed a complex with IL-10, facilitating the extracellular release of IL-10 from DCs. The guanine nucleotide exchange factor MADD (MAPK-activating death domain) was identified as a key regulator of Rab27a activation; knockdown of MADD in DCs eliminated Rab27a activation and IL-10 secretion. Conclusions Activated Rab27a is essential for IL-10 secretion by DCs, and MADD acts as a critical upstream regulator of Rab27a activation. Defects in the MADD-Rab27a-IL-10 signaling pathway contribute to impaired DC tolerogenicity in FA, suggesting that this pathway may serve as a potential therapeutic target for restoring immune balance in allergic diseases.