Skin-derived G-CSF activates pathological granulopoiesis upon psoriasis.

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 the 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 infiltrative into various tissues. We found that upon psoriasis induction, skin-resident endothelial cells are activated to produce G-CSF which contributes to emergency granulopoiesis in bone marrow and cutaneous accumulation of inflammatory neutrophils. Depletion of neutrophils or blockage of psoriasis-driven granulopoiesis by respective neutralizing antibodies lead to the reduction of cutaneous neutrophil burden and mitigates psoriasis pathogenesis. This mechanism appears to be conserved in human psoriasis, confirmed by public RNA-seq database reanalysis. Our findings uncovered and detailed the pathological crosstalk between skin and BM in psoriatic inflammation, proposing a potential therapeutic approach targeting cross-organ communication.