Regulation of epidermal barrier function and pathogenesis of psoriasis by serine protease inhibitors

Abstract

Serine protease inhibitors (Serpins) are a protein superfamily of protease inhibitors that are thought to play a role in the regulation of inflammation, immunity, tumorigenesis, coagulation, blood pressure and cancer metastasis. Serpins is enriched in the skin and play a vital role in modulating the epidermal barrier and maintaining skin homeostasis. Psoriasis is a chronic inflammatory immune-mediated skin disease. At present, most serpins focus on the pathogenesis of psoriasis vulgaris. Only a small number, such as the mutation of SerpinA1/A3/B3, are involved in the pathogenesis of GPP. SerpinA12 and SerpinG1 are significantly elevated in the serum of patients with psoriatic arthritis, but their specific mechanism of action in psoriatic arthritis has not been reported. Some Serpins, including SerpinA12, SerpinB2/B3/B7, play multiple roles in skin barrier function and pathogenesis of psoriasis. The decrease in the expression of SerpinA12, SerpinB7 deficiency and increase in expression of SerpinB3/4 in the skin can promote inflammation and poor differentiation of keratinocyte, with damaged skin barrier. Pso p27, derived from SerpinB3/B4, is an autoantigen that can enhance immune response in psoriasis. SerpinB2 plays a role in maintaining epidermal barrier integrity and inhibiting keratinocyte proliferation. Here we briefly introduce the structure, functional characteristics, expression and distribution of serpins in skin and focus on the regulation of serpins in the epidermal barrier function and the pathogenic role of serpins in psoriasis.

Keywords: hyper-proliferation; inflammation; psoriasis; serine protease inhibitors; skin barrier function.

Figure 1

The 3D structure of SerpinA1. SERPINA1 with labeled structural elements: α helices, β sheet and reactive center loop (RCL).

Figure 2

Schematic representation of the regulatory mechanism of Serpin protein in psoriasis. A neutrophil extracellular trap(NET) structure formed after neutrophil necrosis or apoptosis exposes neutrophil elastase and cathepsin G to the extracellular environment. SerpinA1 and SerpinA3 inhibit neutrophil elastase and cathepsin G, respectively. Normally, elastase and cathepsin G activate IL-36α and IL-36γ, respectively, thereby activating the MAPK and NF-κB signaling pathways of keratinocytes, resulting in increased expression of CXCL1, CXCL2, and IL-8 and increased recruitment of neutrophils. SerpinA12, as an anti-inflammatory factor, is reduced in the skin lesions of psoriasis patients. The reduction of SerpinA12 leads to an overactivation of KLK7 and thus an excessive loss of corneocytes, which impair epidermal barrier. Reduced expression of SerpinA12 in KC reduces keratinocyte differentiation and exacerbates inflammation by reducing the expression of differentiation-related genes and psoriasis related inflammatory gene. The expression of SerpinB2 in keratinocytes is up-regulated under the stimulation of the TNF-α and IFN-γ. As an anti-inflammatory miRNAs, MiR-146a/b collaborates with serpinB2 in keratinocytes to inhibit inflammation in psoriasis. SerpinB2 deficiency leads to upregulation of IL-8, CXCL5 and CCL5 and increased neutrophil migration. SerpinB3/B4 are taken up by mast cells to form Pso p27 through cleavage of chymoenzymes in mast cells. TEAD4 may modulate keratinocyte and T cell crosstalk by targeting SerpinB3/4, thereby affecting keratinocyte and T cell cytokine secretion and T cell migration. SerpinB5 is an autoantigen of an autoimmune response and is the target of an enhanced T-cell response in psoriasis. SerpinB7 deficiency significantly increased the expression of chemokines, neutrophil markers Ly6G, and antimicrobial peptide S100A8, thereby exacerbating skin inflammation. SerpinB7 deficiency inhibits keratinocyte differentiation and promotes the expression of inflammatory mediators by decreasing the calcium ion influx.