Cortistatin Dampens Psoriasis-Like Skin Inflammation Through Interacting with TNF-Α/TNFR1/Nf-κB Signaling Pathway and Regulating Macrophage Polarization

Psoriasis is a common autoimmune disease in clinic. TNF-α/TNFR pathway plays a critical role in inflammatory response of various autoimmune diseases, including psoriasis. Cortistatin (CST), a cyclic neuropeptide, is involved in activation of several types of immune cells, and fights against inflammation procedure. Recently, we found that CST directly binds to TNFR and antagonizes TNF-α function. In this study, IMQ induced psoriasis-like skin inflammation mice models were established in wild type mice, TNFR1-/- mice, TNFR2-/- mice and CST-/- mice, followed by assays of inflammatory response. Moreover, macrophages were isolated from stimulated dorsal skin of wild type mice and CST-/- mice, and macrophage polarization was analyzed. Deficiency of CST led to exaggerated skin inflammation, while exogenous CST attenuated skin inflammatory reaction, which was exhibited by destruction of structure and expression of inflammatory biomarkers in skin. Moreover, IMQ induced psoriasis mice model showed that M1/M2 polarization was altered in deficiency of CST. Furthermore, IMQ induced psoriasis model in CST-/-TNFR1-/- and CST-/-TNFR2-/- mice indicated the role of CST in skin inflammation might rely on interaction with TNFR1. Collectively, CST appears to regulate the polarization of M1/M2 in psoriasis-like skin inflammation via directly bind to TNFR1, which might provide a potential therapeutic target of psoriasis-like skin inflammation. Funding: This work was supported by the Key Research and Development Projects of Shandong Province (Grant No. 2015GSF118115 and 2019GSF108152), the Natural Science Foundation of Shandong Province (Grant No. BS2014YY048, BS2015SW028, ZR2019MH075, ZR2014HM101, and ZR2016HM53), the Cross-disciplinary Fund of Shandong University (Grant No. 2018JC007) and the National Natural Science Foundation of China (Grant No. 81501880 and 81602761). Declaration of Interest: None. Ethical Approval: All experiments concerning animals in this study were approved by the Institutional Animal Care and Use Committee of Shandong University, and performed according to the ARRIVE guideline.