MDI1228, a novel topical small molecule JAK inhibitor, alleviates autoimmune skin diseases by inhibiting dermal fibroblast-T cell interactions

Summary: Abstract Body: The JAK-STAT signaling pathway plays a crucial role in the pathogenesis of various allergic and inflammatory diseases, making it a promising target for the treatment of autoimmune skin diseases. Dermal fibroblasts (dFBs) are pivotal in the skin's innate immune defense and inflammation regulation. However, the distinct activation states of dFBs and their interactions with T cells in different inflammatory contexts are not well understood. In this study, we developed a novel small-molecule JAK inhibitor, MDI1228, and investigated its anti-inflammatory efficacy and mechanism of action in targeting dFBs and T-cell interactions in allergic contact dermatitis (ACD) and atopic dermatitis (AD) mouse models, which are dominated by type I and type II inflammation, respectively. MDI1228 exerted a JAK protein binding activity over 650-fold higher than that of the classical JAK1 inhibitor filgotinib, and it inhibited STAT phosphorylation more than 3-fold higher than that of the classical JAK1/3 inhibitor tofacitinib. Topical application of MDI1228 hydrogel effectively suppressed IFNγ and IL-4/IL-13-induced dermatitis phenotypes and dFB chemotaxis on T cells in ACD and AD mouse models, respectively. In addition, MDI1228 significantly attenuated IFNγ and IL-4/IL-13-mediated activation of mouse or human dFBs in vitro and inhibited the activated dFB-mediated naïve T cell polarization by blocking the IFNγ-CXCL9/10 or IL4/IL13-CCL11 signaling axes. Moreover, long-term application of hydrocortisone, but not MDI1228, resulted in atrophy of the dermal white adipose tissue and immune organs, as well as osteoporosis in mice. In conclusion, the novel pan-JAK inhibitor MDI1228 developed in this study effectively alleviates the development of type I and II autoimmune skin inflammation in mice. Mechanically MDI1228 interferes with the cellular crosstalk between dFBs and T cells. These preclinical results indicate that MDI1228 is a promising candidate for treating type I and/or type II autoimmune skin diseases. Youxi Liu¹, Meimei Yin¹, Yichun Yang¹, Ling-juan Zhang*¹ 1. School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China. Translational Studies: Preclinical