SYK gain-of-function mutation regulates neutrophil functions to drive spontaneous psoriasis

Psoriasis is a chronic, complex autoimmune disease characterized by massive immune cells infiltration including neutrophils. Spleen tyrosine kinase (SYK), a cytoplasmic non-receptor tyrosine kinase, has been reported to be essential to maintain the pro- inflammatory phenotype of neutrophils. Nevertheless, the influence of SYK on neutrophil function under psoriasis remains largely unknown. Here, we employed a SYK gain-of-function (GOF) mutant (SYK ^S544Y ) mouse model to investigate the mechanistic function of SYK activation in the progression of psoriasis. Our findings demonstrate that SYK ^S544Y mice exhibit increased susceptibility to Imiquimod (IMQ) -induced psoriasis and spontaneously develop spontaneous psoriasis-like skin inflammation. SYK activation promotes myeloid cells, particularly neutrophils, infiltration in lesional skin and augments their recruitment activity. Furthermore, inhibition of SYK by R406 has demonstrated therapeutic efficacy on psoriasis. Consequently, these results suggest that SYK activation may contribute to the pathogenesis of psoriasis by augmenting neutrophil recruitment, and targeting SYK may be an attractive strategy to treat psoriasis.