IkappaBzeta in immune cells controls Th17-Th1 balance in imiquimod-induced psoriasis models

Abstract Psoriasis is a chronic inflammatory skin disease in which the IL-23/IL-17 axis and TNFα play crucial roles in disease initiation and persistence. IkBz is a transcriptional regulator that is involved in the expression of the psoriasis-associated genes in keratinocytes. In this study, The aim of this study was to elucidate the contribution of IkBz in immune cells to psoriatic inflammation. We demonstrated that IkBz critically regulates the balance between Th17 and Th1 inflammation in imiquimod-induced psoriasis-model mice. Hematopoietic cell-specific Nfkbiz deficiency (Tie2-Cre) failed to improve clinical severity and epidermal hyperplasia, whereas keratinocyte-specific Nfkbiz deficiency resulted in a marked reduction of these features. Tie2-Cre mice exhibited a shift toward the Th1-dominant inflammatory profile, which was characterized by greatly increased transcription of Th1 cell marker gene Tbx21 as well as the Th1 cell-inducing cytokine Il12a and inflammatory cytokines Il1b , and Tnf , accompanied by reduced expression of Il17a . The expression of Th1 cytokine gene, Ifng , also showed an upward trend. Therapeutic blockage with anti-TNFα and anti-IL-1β antibodies effectively ameliorated the Th1-skewed inflammation observed in Tie2-Cre mice treated with imiquimod. Combined inhibition of TNFα and IL-1β is suggested by these findings to represent a potential therapeutic strategy for psoriasis with Th1-dominant inflammatory features.