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

Background and Purpose: Psoriasis is a common autoimmune skin disease that significantly diminishes patients' quality of life. Interactions between primary afferents of the somatosensory system and the cutaneous immune system mediate the pathogenesis of psoriasis. This study aims to elucidate the molecular mechanisms of how primary sensory neurons regulate psoriasis formation. Experimental Approach: Skin and total RNA were extracted from wild‐type (WT) and ASH1‐like histone lysine methyltransferase (Ash1l+/−) mice in both naive and imiquimod (IMQ)‐induced psoriasis models. Immunohistochemistry, quantitative real‐time polymerase chain reaction (qRT‐PCR) and fluorescence‐activated cell sorting (FACS) were then performed. Microfluidic chamber coculture was used to investigate the interaction between somatosensory neurons and bone marrow dendritic cells (BMDCs) ex vivo. Whole‐cell patch clamp recordings were used to evaluate neuronal excitability after Ash1L haploinsufficiency in primary sensory neurons. Key Results: The 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 dendritic cells (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 DC activation and ameliorates psoriasis. Conclusion and Implications: Somatosensory neuron ASH1L modulates the cutaneous immune system 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. [ABSTRACT FROM AUTHOR]