Anti‐chitinase‐3‐like 1 antibody attenuated atopic dermatitis‐like skin inflammation through inhibition of STAT3‐dependent CXCL8 expression

Abstract

AbstractBackground and PurposeChitinase‐3‐like 1 (CHI3L1) causes skin inflammation in the progression of atopic dermatitis. We investigated if anti‐CHI3L1 antibody could prevent the development of atopic dermatitis and its mechanisms of action.Experimental ApproachThe effect of CHI3L1 antibody on phthalic anhydride‐induced atopic dermatitis animal model and in vitro reconstructed human skin (RHS) model were investigated. Expression and release of atopic dermatitis‐related cytokines were determined using an enzyme‐linked immunosorbent assay, and RT‐qPCR, STAT3 and CXCL8 signalling were measured by western blotting.Key ResultsAnti‐CHI3L1 antibody suppressed phthalic anhydride‐induced epidermal thickening, clinical score, IgE level and infiltration of inflammatory cells, and reduced phthalic anhydride‐induced inflammatory cytokines concentration. In addition, CHI3L1 antibody treatment inhibited the expression of STAT3 activity in phthalic anhydride‐treated skin. It was also confirmed that CHI3L1 antibody treatment alleviated atopic dermatitis‐related inflammation in the RHS model. The inhibitory effects of CHI3L1 antibody was similar or more effective compared with that of the IL‐4 antibody. We further found that CHI3L1 is associated with CXCL8 by protein‐association network analysis. siRNA of CHI3L1 blocked the mRNA levels of CHI3L1, IL‐1β, IL‐4, CXCL8, TSLP, and the expression of CHI3L1 and p‐STAT, and the level of CXCL8, whereas recombinant level of CXCL8 was elevated. Moreover, siRNA of STAT3 reduced the mRNA level of these cytokines. CHI3L1 and p‐STAT3 expression correlated with the reduced CXCL8 level in the RHS in vitro model.Conclusion and ImplicationsOur data demonstrated that CHI3L1 antibody could be a promising effective therapeutic drug for atopic dermatitis.