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MDI1228, a Topical Pan-JAK Inhibitor, Disrupts Dermal Fibroblast-T cell Chemokine Crosstalk to Resolve Autoimmune Skin Diseases

ABSTRACT: Delayed typehypersensitivities are driven by distinct T cell programs and are limited safe long-term topical therapies. Dermal fibroblasts (dFBs) have emerged as active immunomodulators, but whether they can be therapeutically targeted remains unexplored. Here we developed MDI1228, a novel topical pan JAK inhibitor with nanomolar potency against JAK1/2/3/TYK2 (IC50 0.11-0.85 nM) and high selectivity. Topical MDI1228 ameliorated both DNFB induced ACD and MC903 induced AD in mice, reducing T cell infiltration and cytokine production. Mechanistically, MDI1228 not only directly inhibits T cell activation and cytokine production but also disrupts fibroblast-T cell crosstalk by reducing dFB-derived chemokine expression. Single cell transcriptomics identified dFBs as the primary source of CXCL9/10 in ACD and CCL2 in AD. Conditioned medium and neutralization experiments demonstrate that CXCL9/10-CXCR3 and CCL2-CCR2 signaling axes contribute to T cell polarization in a context-dependent manner. Compared with glucocorticoids, prolonged topical application of MDI1228 shows minimal systemic toxicity and preserves tissue homeostasis. These findings identify dFBs as a central therapeutic node and demonstrate that MDI1228, by directly targeting T cells and disrupting dFB derived chemokine axes via JAK inhibition, offers a potent and safe topical treatment for both ACD and AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE308391 | GEO | 2026/07/08

REPOSITORIES: GEO

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MDI1228, a Topical Pan-JAK Inhibitor, Disrupts Dermal Fibroblast-T cell Chemokine Crosstalk to Resolve Autoimmune Skin Diseases

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