TAK1 regulates langerhans cell homeostasis through MAPK and ER stress-activated autophagic machinery.

Summary: Abstract Body: Epidermal Langerhans cells (LCs) are essential for skin homeostasis and the pathogenesis of various diseases. Recent fate-mapping studies have shown that LCs originate prenatally from the yolk sac and fetal liver precursors. These cells undergo self-maintenance throughout life and regenerate from the bone marrow (BM) under stress conditions. While the role of TAK1 in cell survival is well-established, its specific function in LCs and the underlying molecular mechanisms remain unclear. In this study, we aimed to investigate the role of TAK1 in postnatal LC maintenance using CD11ccre mediated TAK1 deletion mice. Our results revealed a significant reduction in steady-state LC number, LC maturation (CD80, CD86, CD40) and antigen uptake function upon TAK1 deletion, highlighting the critical role of TAK1 in both LC maintenance and function. Interestingly, TAK1 deletion had no effect on BM-derived LC repopulation after UVC exposure. Furthermore, TAK1-deleted LCs exhibited increased autophagy (LC3B) and apoptosis (Annexin V), suggesting that TAK1 plays a crucial role in regulating both autophagy and cell death. Mechanistically, this autophagic response is triggered by the induction of ER stress (HSPA5, ERN1, INSIG1, PERK) and the downregulation of MAPK pathways (pP38, pERK, pJNK) and their downstream target (pP65), culminating in the upregulation of autophagy regulatory genes (Uvrag, P62) that mediate cell death. In conclusion, our data suggest that TAK1 regulates ER stress and MAPK-mediated autophagic cell death, thereby maintaining LC homeostasis and function under steady-state conditions. However, TAK1 appears dispensable for BM-derived LC repopulation under inflammatory conditions. Nirmal Parajuli¹, Qiyan Wang², Qian Yu¹, Qing-Sheng Mi¹, Li Zhou¹ 1. Dermatology, Henry Ford Health System, Detroit, MI, United States. 2. Dermatology, Henry Ford Health System, Detroit, MI, United States. Innate Immunity, Microbiology, and Microbiome