Skin-derived G-CSF activates pathological granulopoiesis upon psoriasis

Abstract

Psoriasis is an inflammatory skin disease initiated by environmental triggers and driven by disruption of T cell cytokine network in the cutaneous milieu. The fact that complete resolution of disease by targeting key inflammatory cytokines remains challenging indicates a contribution of other immune cells to the pathogenesis. Here, we study the role of neutrophils in psoriasis, the first-line innate immune defender that is short-lived but mobile and infiltrate into various tissues. We found that upon psoriasis induction, skin-resident endothelial cells are activated to produce G-CSF which activates emergency granulopoiesis in bone marrow and induces cutaneous infiltration and accumulation of neutrophil that are functionally overactive. Depletion of neutrophils or blockage of psoriasis-driven granulopoiesis by respective neutralizing antibodies results in reducing cutaneous neutrophil burden and mitigating psoriasis pathogenesis. This mechanism might be conserved in human psoriasis as confirmed by public RNA-seq database. Our findings uncovered and detailed the pathological crosstalk between skin and BM in psoriatic inflammation, proposing a potential therapeutic approach targeting cross-organ communication.