Tannic acid inhibits TNF-α signaling by targeting the protein disulfide isomerase and alleviates symptoms in an imiquimod-induced psoriasis mouse model

Inhibiting TNF-α signaling is an effective approach to prevent inflammation, which can mitigate the symptoms of autoimmune diseases. Activation of the ADAM17-TNFR1 signaling module using small-molecule protein disulfide isomerase (PDI) inhibitors effectively induces TNFR1 shedding and TNF-α signaling inhibition. However, it is not known whether tannic acid (TA), a verified PDI inhibitor with outstanding anti-inflammatory effects, could alleviate autoimmune diseases. We set out to explore the anti-inflammatory mechanism of TA and whether it could be used to treat the classical autoimmune disease, psoriasis. Molecular interactions were assessed using insulin reduction assays with full-length PDI and its domain fragments to identify TA binding sites. Non-covalent binding and conformational changes were evaluated using AMS-modified SDS-PAGE and ANS fluorescence. Molecular chaperone activity was measured using rhodanese refolding. Cellular assays included cytotoxicity, apoptosis, and NF-κB activation in L929 cells using CCK-8, flow cytometry, western blot, and RT-qPCR. PDI dependency was confirmed using CRISPR-Cas9 knockout. TNFR1 shedding was quantified using flow cytometry and ELISA. In vivo efficacy was tested in an imiquimod (IMQ)-induced psoriasis mouse model treated with TA ointment (5% and 10%), and the outcomes were evaluated using the psoriasis area and severity index (PASI), histopathology, blood routines, and blood biochemical examinations. TA selectively inhibited the reductase activity of the bʹ domain of PDI and induced non-covalent conformational changes, reducing hydrophobicity and chaperone function. TA effectively suppressed TNF-α-induced apoptosis in cells, NF-κB activation, and inflammatory gene expression. PDI knockout abolished TA-induced TNFR1 shedding, confirming PDI dependence. In IMQ-induced psoriatic mice, 10% TA ointment significantly reduced the PASI scores and the incidence of histopathological features. TA also normalized blood inflammation and restored physical functions. In summary, our study showed that TA blocks TNF-α signaling by inhibiting PDI, and exhibits potential application value in combating autoimmune diseases, especially psoriasis.