Loss of kallikrein 5 expression exacerbates allergic skin inflammation including impairing filaggrin processing, promoting Th2 differentiation and inducing dysbiosis.

Atopic dermatitis (AD) is a chronic allergic skin disease with T helper 2 (Th2) cell predominance and epithelial barrier impairment. The serine protease kallikrein (KLK) 5 has an essential role in regulating keratinocyte desquamation and skin renewal. Increased expression and activity of KLK5 is sufficient to induce skin inflammatory responses including AD. We examined the consequences of Klk5 deficiency following exposures to the type 2-provoking agent calcipotriol in mice. Loss of KLK5 exacerbates a spectrum of AD-like responses including increased accumulation of skin eosinophils and langerhans cells, over-expression of an array of cytokines in the skin and exacerbated scratching behavior. Klk5-/- mice demonstrated microbiome dysbiosis with enriched actinobacteria and reduced firmicutes in the skin, alteration in skin metabolites involved in the acetyl-CoA pathway and decreased expression of mature filaggrin monomers. Cutaneous application of Cis-Urocanic acid (cUCA) attenuated inflammatory responses, highlighting barrier dysfunction as a primary mechanism. We reveal an unappreciated role for KLK5 in inhibiting type 2 responses, acting through its roles in filaggrin processing and modulation of the skin microbiome and metabolome. Though KLK5 overactivation is known to contribute to several inflammatory skin disorders, our findings demonstrate that complete loss of KLK5 is also pathogenic in AD-like responses in mice.