Transforming growth factor β-activated kinase 1 (TAK1) modulates Langerhans cells (LCs) homeostasis through endoplasmic reticulum (ER) stress-induced autophagy.

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Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B694
Abstract ID: 4489

Presenting Author:
Nirmal Parajuli , Research Scientist at Henry Ford Hlth., Henry Ford Hlth.

Abstract:

Epidermal LCs are crucial for skin homeostasis and disease pathogenesis. Recent fate mapping studies reveal LCs originate prenatally from the yolk sac and fetal liver. These cells undergo self-maintenance throughout life and regenerate from bone marrow (BM) under stress condition. Despite the emeriging role of TAK1 in cell survival, its specific function in LCs and underlying molecular mechanisms remain unclear. In this study, we aimed to investigate TAK1's role in postnatal LC maintenance using dendritic lineage CD11c^cre  specific TAK1 deletion mice. Our findings showed a significant reduction in steady-state LCs, LC maturation markers (CD80, CD86, CD40), and LC antigen uptake upon TAK1 deletion, emphasizing the crucial role of TAK1 for LCs and their function. Intriguingly, TAK1 deletion showed no effect BM-derived LC repopulation after UVC exposure. Additionally, TAK1-deleted LCs exhibit increased cellular autophagy (LC3B) and apoptosis (Annexin V), implying a crucial role of TAK1 in autophagy including cell death. Mechanistically, this autophagic response is driven by induced ER stress enhanced markers (HSPA5, ERN1, INSIG1, PERK), culminating in increased expressions of autophagy regulatory genes (Uvrag, P62) for mediating cell death. In conclusion, our data suggest that TAK1 controls ER stress-mediated autophagic cell death, thereby maintains LC homeostasis and function under steady-state conditions, while being dispensable for LCs in BM-derived inflammatory conditions.