TDM-induced trained immunity reprograms hematopoietic stem cells to modulate cutaneous inflammatory responses 2870

Abstract Description Trained immunity refers to the long-term reprogramming of innate immune cells and their progenitors, enabling altered, often heightened responses to subsequent immune challenges. This adaptive-like behavior in the innate immune system has major implications for inflammatory diseases. Atopic dermatitis and psoriasis, two common inflammatory skin disorders with distinct immune profiles, serve as valuable models for studying immune modulation. In this study, we investigated how trehalose dimycolate (TDM), a mycobacterial glycolipid that induces trained immunity, affects immune lineage differentiation and disease progression in these models. Following intravenous TDM administration, mice were challenged with atopic dermatitis and psoriasis models, resulting in reduced atopic dermatitis symptoms but worsened psoriasis. To explore how TDM reprograms immune responses, we conducted ATAC-seq and RNA-seq on lineage-negative hematopoietic stem cells (HSCs) isolated from bone marrow across multiple time points post-TDM exposure. Our findings indicate that TDM biases HSC lineage, favoring lymphoid over myeloid differentiation. This TDM-driven trained immunity effect establishes durable immune memory in progenitor cells, potentially explaining these divergent disease effects. These insights emphasize trained immunity’s role in immune modulation, highlighting TDM’s potential to reshape disease outcomes through innate immune memory. Funding Sources This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT) (NRF-2023R1A2C1005804, RS-2024-00408822) Topic Categories Hematopoiesis and Immune System Development (HEM)