Type 2 Immune Response Plays A Critical Role in Trained Immunity

Abstract Trained immunity, or innate immune memory, is vital in inducing heterologous protection against infection. Type 2 cytokines such as IL-4 and IL-13 induce M2 macrophage differentiation, characterized by anti-inflammatory phenotype permitting inflammation resolution and wound healing. Here we report that peritoneal macrophages isolated from OVA-allergen sensitized mice possessed both M2 signatures and a pro-inflammatory phenotype. Moreover, mice were more resistant to bacterial infection in the OVA-induced allergy model. Mechanistically, we found that IL-4 induced trained immunity in a STAT6-independent and IRS-dependent manner. Furthermore, IL-4 induces epigenetic memory in the pro-inflammatory gene enhancer regions, ensuring a higher transcription activity upon stimulation. In addition, IL-4 trained macrophages are metabolically more glycolytic upon LPS stimulation. To conclude, this unrecognized role of IL-4 in trained immunity broadens our understanding of IL-4 mediated physiological changes and provides immediate impacts on how type 2 immune response could re-direct disease progression in response to pathogen infection.