Ash1L ameliorates psoriasis via limiting neuronal activity‐dependent release of miR‐let‐7b

Abstract

Background and PurposePsoriasis is a common autoimmune skin disease which significantly diminishes patients’ quality of life. Primary afferents of the somatosensory system and cutaneous immune system interaction essentially mediates the pathogenesis of psoriasis. This study aims to elucidate the molecular mechanism for how primary sensory neurons regulate psoriasis formation.Experimental ApproachSkin and total RNA was extracted from WT and Ash1l+/‐ (ASH1 like histone lysine methyltransferase) mice in both naïve and IMQ (Imiquimod)‐induced psoriasis model conditions. Immunohistochemistry, qRT‐PCR and FACS were then performed. Microfluidic chamber coculture was used to investigate the interaction between somatosensory sensory neurons and bone marrow dendritic cells (BMDCs) ex vivo. Whole‐cell patch clamp recordings was used to evaluate neuronal excitability after Ash1L haploinsufficiency in primary sensory neurons.Key ResultsThe haploinsufficiency of ASH1L, a histone methyltransferase, in primary sensory neurons causes both neurite hyperinnervation and increased neuronal excitability, which promote miR‐let‐7b release from primary afferents in the skin in a neuronal activity‐dependent manner. With a “GUUGUGU” core sequence, miR‐let‐7b functions as an endogenous ligand of Toll‐like receptor 7 (TLR7) and stimulates the activation of dermal DCs and interleukin (IL)‐23/IL‐17 axis, ultimately exacerbating the symptoms of psoriasis. Thus, by limiting miR‐let‐7b release from primary afferents, ASH1L prevents dermal DCs activation and ameliorates psoriasis.Conclusion and ImplicationsSomatosensory neuron ASH1L modulates cutaneous immune by limiting neuronal activity‐dependent release of miR‐let‐7b, which can directly activate dermal DCs via TLR7 and ultimately lead to aggravated psoriatic lesion.