Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism

ABSTRACT Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related ( Atg ) genes, prevents accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs), a proliferating skin DC subset with extended lifespan. Here, we demonstrate that deletion of either Atg5 or Atg7 in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Metabolically impaired LCs upregulated proinflammatory transcripts, in line with exacerbated inflammasome-dependent priming. Moreover, they decreased expression of neuronal interaction receptors, in line with a reduction of epidermal nerves upon LC depletion. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis