REG family proteins and immune regulation: current evidence and perspectives

As a group of small secretory proteins widely expressed in digestive and nondigestive tissues, the regenerating islet-derived (REG) family members have been highlighted for their multifunctional properties, such as pro-proliferative, mitogenic, anti-apoptotic, differentiation-inducing, anti-inflammatory, bactericidal, anti-oxidation and pro-tissue-repair activities. Emerging evidence indicates context-dependent immunomodulatory potentials of specific REG proteins. This review focused on the involvement and potential roles of REG family proteins in regulating immune cells. Available data suggest that individual REG members, including human REG4/murine Reg4, specific REG3/Reg3 subfamily isoforms, and murine Reg2, exert heterogeneous regulatory effects on macrophage migration, recruitment, proliferation, and function. The immunomodulatory impacts of REG3/Reg3 subfamily members on dendritic cell phenotype and function have recently been uncovered in pancreatic carcinogenesis and autoimmune diabetic models. Certain REG proteins also exhibit context-dependent modulatory effects on T cell and neutrophil responses, though current observations remain fragmentary. Research regarding REG-mediated immune regulation is still in its infancy, with undefined cellular receptors, ambiguous direct targets, and incompletely resolved signaling mechanisms. Further mechanistic validation is therefore required before the translational potential of REG-based immunotherapies for inflammatory and immunological diseases can be reliably evaluated.