IL-31 suppresses the expression of TARC/CCL17 in TNF-alpha/IFN-gamma-stimulated HaCaT keratinocytes

The most common symptom of atopic dermatitis (AD) is itching, which results in sleep disturbances and psychological stress, substantially reducing the quality of life of patients. Nemolizumab is a monoclonal antibody targeting interleukin 31 receptor A (IL-31RA) and mitigates the itching in AD by inhibiting the activity of IL-31, a cytokine mainly produced by T helper 2 cells. However, elevated levels of thymus and activation-regulated chemokine (TARC)/C–C motif chemokine ligand 17 (CCL17), a marker for disease severity in AD, were observed in some patients with AD following nemolizumab administration, although these patients almost did not exhibit an exacerbation of AD symptoms. This study aimed to elucidate the possible mechanism underlying the upregulation of CCL17 with nemolizumab treatment in some patients. We evaluated the effects of IL-31 and nemolizumab on the mRNA expression of CCL17 in TNF-alpha/IFN-gamma-stimulated HaCaT keratinocytes in vitro using qRT-PCR. In addition, we comprehensively analyzed the impact of IL-31 and nemolizumab on keratinocyte-related phenomena, using RNA sequencing. Our findings indicated that IL-31 suppressed the expression of CCL17 mRNA in keratinocytes, and nemolizumab reversed this suppressive effect. We further discovered that although oncostatin M suppressed the expression of CCL17 mRNA, its action was unaffected by nemolizumab. Furthermore, IL-31 affected keratinocyte differentiation, lipid metabolism, and inflammatory cytokine. Herein, we propose a possible mechanism by which nemolizumab counteracts the inhibitory effect of IL-31 on CCL17 expression, thus explaining the increased CCL17 levels following nemolizumab administration in some patients with AD.