{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE308nnn/GSE308391/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE308391"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"MDI1228, a Topical Pan-JAK Inhibitor, Disrupts Dermal Fibroblast-T cell Chemokine Crosstalk to Resolve Autoimmune Skin Diseases","description":"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.","dates":{"publication":"2026/07/08"},"accession":"GSE308391","cross_references":{"GSM":["GSM9244527","GSM9244526"],"GPL":["24247"],"GSE":["308391"],"taxon":["Mus musculus"],"PMID":["[42548722]"]}}