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Several inflammatory diseases are reported to be regulated by proline\u2010rich tyrosine kinase 2B (PTK2B). However, the role of PTK2B in regulating the function of neutrophils and the pathogenesis of UC remains unknown. In this study, the mRNA and protein levels of PTK2B in the colonic tissues from UC patients were measured by using quantitative real\u2010time polymerase chain reaction (qRT\u2010PCR), western blotting, and immunohistochemistry. TAE226, a PTK2B inhibitor, was used to inhibit the activity of PTK2B in neutrophils, and then, the pro\u2010inflammatory factors were analyzed by using qRT\u2010PCR and ELISA. To determine the role of PTK2B in intestinal inflammation, a dextran sulfate sodium (DSS)\u2010induced colitis model was established in PTK2B gene knockout (PTK2B KO) and wild\u2010type (WT) mice. We found that compared with healthy donor controls, the expression level of PTK2B was significantly elevated in inflamed mucosa from UC patients. In addition, expression of PTK2B was positively correlated with the severity of disease. Pharmacological inhibition of PTK2B could markedly reduce the generation of reactive oxygen species (ROS), myeloperoxidase (MPO), and antimicrobial peptides (S100a8 and S100a9) in neutrophils. The vitro study showed that tumor necrosis factor (TNF)\u2010\u03b1 is involved in promoting the expression of PTK2B in neutrophils. As expected, UC patients treated with infliximab, an anti\u2010TNF\u2010\u03b1 agent, showed significantly reduced level of PTK2B in neutrophils, as well as in the intestinal mucosa. Of note, compared with DSS\u2010treated WT mice, DSS\u2010treated PTK2B KO mice showed more severe colitis symptoms. Mechanistically, PTK2B could enhance neutrophil migration by regulating CXCR2 and GRK2 expression via the p38 MAPK pathway. Additionally, mice treated with TAE226 exhibited the same effects. In conclusion, PTK2B is involved in the pathogenesis of UC by promoting the migration of neutrophils and inhibiting mucosal inflammation, highlighting PTK2B as a new potential therapeutic target to treat UC.<\/jats:p>","DOI":"10.1096\/fj.202201995rr","type":"journal-article","created":{"date-parts":[[2023,6,3]],"date-time":"2023-06-03T03:06:59Z","timestamp":1685761619000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["<scp>PTK2B<\/scp>\n                    regulates immune responses of neutrophils and protects mucosal inflammation in ulcerative colitis"],"prefix":"10.1096","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7803-605X","authenticated-orcid":false,"given":"Guangxi","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Affiliated Hospital of Jining Medical University, Jining Medical University  Jining P.R. 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