Tranexamic acid blocks the thrombin-mediated delay of epidermal permeability barrier recovery induced by the cedar pollen allergen, Cry j1

S Nakanishi,M Denda,J Kumamoto

doi:10.1038/s41598-018-33898-7

Abstract

We previously demonstrated that Cry j1, the major pollen allergen of Cryptomeria japonica (Japanese cedar), transiently increases protease activity and intracellular Ca2+ concentration in cultured human keratinocytes, and delays recovery after stratum corneum barrier disruption in human skin ex vivo. Topical application of tranexamic acid or trypsin-type serine protease inhibitors accelerates barrier recovery. We hypothesized that tranexamic acid might prevent the transient protease activity increase and the barrier recovery delay induced by Cry j1. Here, we tested this hypothesis and examined the mechanism involved. In cultured human keratinocytes, knock-down of protease-activated receptor 1 (PAR-1) reduced the transient increase of calcium induced by Cry j1, whereas knock-down of PAR-2 did not. Knock-down of thrombin significantly reduced the transient increases of calcium concentration and protease activity. Tranexamic acid, soybean trypsin inhibitor, or bivalirudin (a thrombin inhibitor) also reduced the calcium elevation induced by Cry j1 and/or thrombin. Co-application of tranexamic acid or bivalirudin with Cry j1 to human skin ex vivo blocked the delay of barrier recovery. These results suggest that thrombin and PAR-1 or PAR-1-like receptor might mediate the adverse effects of Cry j1 on human epidermal keratinocytes, and could open up a new strategy for treating inflammatory skin diseases.

Highlights

We previously demonstrated that the major Japanese cedar (Cryptomeria japonica) pollen allergen, Cry j1, perturbs epidermal permeability barrier recovery after disruption[1]
We found here that plasmin/plasminogen expression is undetectable in keratinocytes, and instead, tranexamic acid appears to block the adverse effects of Cry j1 on keratinocytes and epidermal permeability barrier homeostasis via a pathway involving thrombin and protease-activated receptor 1 (PAR-1) or a PAR1-like receptor
Based on previous studies showing that urokinase-type plasminogen activator is associated with barrier function in human skin[5,6] and that tranexamic acid, a plasminogen inhibitor, accelerates skin barrier recovery[2,7], we initially expected that the impairment of human skin barrier function by Cry j1 would be due to plasminogen activation

Summary

Introduction

We previously demonstrated that the major Japanese cedar (Cryptomeria japonica) pollen allergen, Cry j1, perturbs epidermal permeability barrier recovery after disruption[1]. Inhibitors of trypsin-type serine protease and protease-activated receptor 2 (PAR-2) reduced the calcium elevation, and topical application of the inhibitors after barrier disruption in an ex-vivo human skin system decreased the Cry j1-induced delay of the barrier recovery[1]. Protease activity was transiently increased in the epidermis after barrier disruption, and tranexamic acid partially blocked this increase Based on these observations, we hypothesized that application of tranexamic acid might prevent the increase of protease activity and reduce the delay of barrier recovery induced by Cry j1. We found here that plasmin/plasminogen expression is undetectable in keratinocytes, and instead, tranexamic acid appears to block the adverse effects of Cry j1 on keratinocytes and epidermal permeability barrier homeostasis via a pathway involving thrombin and protease-activated receptor 1 (PAR-1) or a PAR1-like receptor. Thrombin and PAR-1 or the PAR-1-like receptor may be available as new therapeutic targets to improve epidermal barrier homeostasis in the presence of harmful environmental factors such as Cry j1

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