Secretory leukocyte protease inhibitor regulates nerve reflex‐mediated skin barrier function in psoriasis

BACKGROUND: Secretory leukocyte protease inhibitor (SLPI), a ~12 kDa protein is an important regulator of innate and adaptive immunity and a component of tissue regenerative programmes. SLPI expression is markedly elevated in chronically inflamed skin, including that of individuals suffering from psoriasis. However, the role of SLPI in these diseases remains elusive. OBJECTIVES: The poor understanding of the early stages of the development of psoriasis is a major obstacle to successful intervention in the skin pathology. We hypothesized that SLPI and peripheral nerves that might be activated early in the progression of the disease likely form a functional relationship to maintain skin barrier homeostasis and respond to a variety of threats. METHODS: We used skin biopsies of healthy donors and individuals with psoriasis to show expression pattern of SLPI. A role of SLPI in psoriasis was mechanistically assessed using SLPI‐deficient mice and an imiquimod (IMQ)‐induced experimental model of psoriasis. RESULTS: We show that mice lacking SLPI had exaggerated skin alterations that extended beyond the treatment site in an imiquimod‐induced psoriasis. The spatiotemporally distinct skin responses in SLPI‐deficient mice, compared to their wild‐type littermates, resulted from a compromised skin barrier function that manifested itself in heightened transepidermal water loss through the larger skin area surrounding the IMQ‐challenged skin. The increased pathogenic skin changes in the absence of SLPI were reversible through pharmacological treatment that blocks a nerve‐reflex arc. CONCLUSIONS: Together, these data indicate that SLPI plays a protective role in psoriasis through preventing skin dryness, inherent in the pathogenesis of psoriasis and that this SLPI action depends on neuronal input operating in a reflex manner. These findings reveal a previously unrecognized mechanism that maintains cutaneous homeostasis, which involves a crosstalk between the nervous system and a protein anatomically poised to fortify the epidermal permeability barrier.