Abstract Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent mucosal inflammation and immune dysregulation. Dysregulated macrophage polarization is a central driver of immune imbalance in UC. Lipocalin-2 (LCN2), a natural immune-related protein, is upregulated in UC patients. However, its pro-inflammatory role and relationship with macrophage polarization remain unclear. Methods We explored the role of LCN2 in UC through clinical, animal, and cellular studies. Serum and colonic mucosa samples from healthy volunteers and active UC patients were collected to assess LCN2 expression via ELISA and immunohistochemistry. UC was induced in wild-type and LCN2-knockout mice using dextran sulfate sodium (DSS). Transcriptomic analysis, Western blotting, and immunofluorescence were used to evaluate LCN2 expression, localization, and function. Bone marrow-derived macrophages (BMDMs) from WT and LCN2-/- mice were stimulated with M-CSF and LPS, and the expression of the LCN2 receptor SLC22A17, M1 markers, inflammatory cytokines, and NF-κB pathway activation were analyzed. Results LCN2 expression was significantly upregulated in UC patients and DSS-treated mice. LCN2 binds to the macrophage receptor SLC22A17, activates the NF-κB pathway, promotes M1 polarization, and enhances the release of pro-inflammatory cytokines. LCN2 deficiency alleviated colonic inflammation and pathology in DSS-treated mice, reduced macrophage infiltration and M1 polarization, and decreased inflammatory factors expression by inhibiting SLC22A17 internalization and NF-κB. Conclusion This study reveals a novel mechanism by which LCN2 aggravates colitis by promoting pro inflammatory macrophage polarization. LCN2 may serve as a biomarker for UC severity and a potential therapeutic target via its interaction with SLC22A17 and activation of NF-κB signaling. Conflict of interest: Xu, Yan: No conflict of interest Mr. Huang, Junwei: No conflict of interest Chen, Wei: No conflict of interest Niu, Mengdi: No conflict of interest Chen, Miaodan: No conflict of interest Han, Yixuan: No conflict of interest Sun, Lixin: No conflict of interest Wang, Qiang: No conflict of interest Jiao, Chunhua: No conflict of interest
Xu et al. (Thu,) studied this question.