Erschienen in:
British Journal of Pharmacology, 181 (2024) 7, Seite 1107-1127
Sprache:
Englisch
DOI:
10.1111/bph.16254
ISSN:
0007-1188;
1476-5381
Entstehung:
Anmerkungen:
Beschreibung:
Background and PurposePsoriasis 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 ApproachSkin 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 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 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 ImplicationsSomatosensory 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.