Transforming Growth Factor β-activated Kinase 1 Controls Langerhans Cell Homeostasis through Autophagic Machinery
Recommended Citation
Parajuli N, Wang Q, Yu Q, Ge J, Mi Q, Zhou L. Transforming Growth Factor β-activated Kinase 1 Controls Langerhans Cell Homeostasis through Autophagic Machinery. J Invest Dermatol 2024; 144:S173.
Document Type
Conference Proceeding
Publication Date
8-1-2024
Publication Title
J Invest Dermatol
Abstract
Epidermal LCs play a vital role in skin homeostasis and disease pathogenesis. Fate mapping studies, including those from our group and others, have revealed that LCs originate from primitive yolk sac and fetal liver hematopoiesis. During steady stages, LCs undergo self-maintenance, while in stress conditions they regenerate via bone marrow (BM). Among the few well-identified genes for epidermal LCs, transforming growth factor-β1 (TGF-β1) stands out crucial. Notably, recent research emphasized TGF-β1 downstream TAK1 governs cellular viability. However, the underlying molecular mechanisms, phenotype, and functional requirements following TAK1 deletion in LCs remain unclear. Hence, we hypothesize that TAK1 plays a pivotal role in LC development and function, and its absence may trigger diverse molecular cascades, influencing both phenotype and function. To investigate this, we generated TAK1 deletion mice by crossing TAK1flox/flox mice with dendritic-specific CD11ccre mice, and evaluated the phenotype and function of LCs using flow cytometry, bulk RNA sequencing, and Western blot analyses. At steady state, the frequencies of epidermal LCs were significantly reduced. Functionally, LC maturation markers (CD80, CD86, CD40) and LC antigen uptake ability were decreased upon TAK1 deletion. However, TAK1 deletion showed no effect BM-derived LC repopulation after UVC exposure. TAK1-deleted LCs exhibited increased cellular autophagy (LC3-II) and apoptosis (Annexin V). Mechanistically, TAK1 deletion led to induction of ER stress markers (HSPA5, ERN1, INSIG1, PERK) and decreased phosphorylation of MAPK kinases (P38, ERK1/2, JNK1/2) including NFkB and mTOR, culminating an increased expressions of autophagy regulatory genes (Uvrag, P62), and mediating autophagic cell death in LCs. Overall, our data suggest that TAK1 controls various MAPK kinases, including ER stress, to mediate autophagic cell death, maintaining LC homeostasis and function under steady-state conditions, but dispensable for LC repopulation under inflammatory conditions.
Volume
144
First Page
S173
