Aryl hydrocarbon receptor knockdown in langerhans cells attenuates psoriatic inflammation by increasing IL-10 but not IDO-1, plausibly through autophagy regulation

Summary: Abstract Body: Topical medication targeting aryl hydrocarbon receptor (AhR), an environmental sensor, is approved to treat psoriasis. We have shown that specific AhR ablation in epidermal Langerhans cells (LC) decreases LC numbers while induces Th2/Tr1 polarization in atopic sensitization. However, how AhR in LC regulates pathophysiology of psoriasis remains unclear. We measured AhR expression in LC in human psoriasis. We tested the imiquimod induced psoriasis in langerin-specific AhR knockout mice (Langerin-AhR-/-). In human psoriasis, there are fewer CD207-expressing LC, and most AhR is located in cytosol. Interestingly, these CD207+ cells express LC3b, a marker for autophagy. In imiquimod-induced psoriasis, epidermal thickening was significantly decreased in Langerin-AhR-/- mice. The numbers of bone marrow derived Langerhans cell like cells (BMLC) from Langerin-AhR-/-mice are decreased. BMLC from WT mice treated with AhR inhibitor (CH223191) or from Langerin-AhR-/- showed an increase in IL-10, decreases in IL-1b and IDO-1, with no difference in the IL-23, CGRP, beta-endorphin (by ELISA and real time PCR) and slightly increased expression in the costimulatory markers CD80, CD86, and MHC-II (by flow cytometry). Meanwhile, these BMLC with defected AhR showed attenuated autophagy with late induction of p62. The increased IL-10 and decreased in IL-1b in BMLC from Langerin-AhR-/- or BMLC from WT mice treated with CH223191 are attenuated by treatment with rapamycin, an autophagy inducer. In summary, we showed that AhR blockage in LC showed an attenuated psoriatic inflammation, by increasing IL-10 and decreasing IL-1b (but not IDO-1, an anti-inflammatory mediator), potentially through autophagy mechanisms. AhR may coordinate with autophagy in LC, contributing to the development of psoriasis. Chien-Hui Hong^{1, 2}, Chih-Hung Lee^{3, 4} 1. Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. 2. Dermatology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan. 3. Dermatology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. 4. Dermatology, Chang Gung University College of Medicine, Taoyuan, Taiwan. Innate Immunity, Microbiology, and Microbiome