Abstract
Psoriasis is a common inflammatory skin disease resulting from an interplay of keratinocytes and immune cells. Previous studies have identified an essential role of autophagy in the maintenance of epidermal homeostasis including proliferation and differentiation. However, much less is known about the role of autophagy-related proteins in the cutaneous immune response. Herein, we showed that ULK1, the key autophagic initiator, and its phosphorylation at Ser556 were distinctively decreased in the epidermis from lesional skin of psoriasis patients. Topical application of SBI0206965, a selective ULK1 inhibitor, significantly attenuated epidermal hyperplasia, infiltration of neutrophils, and transcripts of the psoriasis-related markers in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD). In vitro, ULK1 impairment by siRNA and SBI0206965 arrested cell proliferation and promoted apoptosis of keratinocytes but had a marginal effect on the expression of proinflammatory mediators under steady status. Surprisingly, SBI0206965 blocked the production of chemokines and cytokines in keratinocytes stimulated by neutrophils. Of interest, the pro-apoptotic and anti-inflammatory effects of ULK1 inhibition cannot be fully replicated by autophagic inhibitors. Our findings suggest a self-regulatory process by downregulating ULK1 to maintain the immune homeostasis of psoriatic skin via regulating keratinocytes and their crosstalk with neutrophils, possibly through both autophagy-dependent and independent mechanisms. ULK1 might be a potential target for preventing or treating psoriasis.
Highlights
Psoriasis is characterized by keratinocyte hyperproliferation and infiltration of immune cells in inflamed skin [1]
Neutrophil-keratinocyte crosstalk is an early target of IL-17A antibody-mediated therapies in psoriasis [9], suggesting that communication of keratinocytes and neutrophils is involved in the immunopathogenesis of psoriasis
Unc-51 like autophagy activating kinase 1 (ULK1) was involved in autophagy by integrating the upstream signals of anti-microbial peptides (AMPs)-activated protein kinase (AMPK) and transducing them to the downstream autophagy pathway [26]
Summary
Psoriasis is characterized by keratinocyte hyperproliferation and infiltration of immune cells in inflamed skin [1]. Keratinocytes overproduce antimicrobial peptides (AMP), cytokines of the IL-1 family together with chemokines to recruit and activate innate immune cells such as neutrophils, mast cells, macrophages, and plasmacytoid dendritic cells (pDC) in response to the upstream triggers [3, 4]. Infiltrated immune cells, in return, stimulate KCs, which undergo dysregulated proliferation and differentiation, and at the same time, produce more chemokines (such as CCL20, CXCL1, CXCL2 and CXCL8) and AMP (such as S100 proteins and b-defensins) to magnify the immune circuits responsible for the induction and maintenance of psoriasis. NETs further supply IL-17 and induce T helper 17 (Th17) cells to release more cytokines, bridging the innate immune and adaptive immune systems [8]. Neutrophil-keratinocyte crosstalk is an early target of IL-17A antibody-mediated therapies in psoriasis [9], suggesting that communication of keratinocytes and neutrophils is involved in the immunopathogenesis of psoriasis
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