350 Histone demethylase LSD1 is required for LC embryonic development but dispensable for LC maintenance and repopulation

Abstract

Langerhans cells (LCs), the sole dendritic cell subpopulation in the epidermis, are potent regulators of immune surveillance and tolerance. Unlike conventional DCs, LCs follow unique patterns of development and maintenance under steady and inflamed states. Lysine-specific demethylase 1 (LSD1), known to mediate the demethylation of lysine amino acids on histone proteins, plays a key role in the maintenance and differentiation of hematopoietic stem cells. However, the role of LSD1 in LC ontogeny and homeostasis remains unknown. To address this, we generated Csf1rCreLSD1fl/fl conditional knockout (Csf1r.LSD1-KO) mice in which LSD1 was deficient in macrophage/monocytes and LC precursors from embryonic stage. We found a robust reduction of LC precursors in Csf1r.LSD1-KO mice at embryonic day 18.5 and postnatal day 0, suggesting that LSD1 is required for LC ontogeny at late embryonic stage. To investigate whether LSD1 is involved in LC maintenance and repopulation, we created CD11cCreLSD1fl/fl conditional knockout (CD11c.LSD1-KO) mice in which LSD1 was deficient in all DC populations including epidermal LCs after birth. Flow cytometry and immunofluorescent staining of skin showed that the frequency and number of LCs were unaltered in 2-week-old and adult CD11c.LSD1-KO mice compared to wild-type mice. Using an ultraviolet C (UVC)-induced skin damage model, we found that long-term LCs were able to repopulate to the inflamed epidermis of CD11c.LSD1-KO mice 2 weeks after UVC treatment. Overall, our data suggests that LSD1 is critical for LC embryonic development, but not required for the LC maintenance at steady state and repopulation under inflammatory conditions.