A macrophage-targeted TIMD4 Peptide-Nanoparticle attenuates colitis symptoms and monocyte recruitment in a mouse...

Macrophages play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). T-cell immunoglobulin and mucin domain-containing molecule 4 (TIMD4) is involved in the regulation of tissue-resident macrophages. TIMD4 expression is elevated in colonic tissues from patients with ulcerative colitis (UC) and mice with dextran sulfate sodium (DSS)-induced colitis, but its role in IBD pathogenesis remains unclear. In this study, we found that Timd4 deficiency aggravated DSS-induced colitis, accompanied by increased infiltration of monocytes into the colonic tissues. Treatment with a CCR2 antagonist attenuated colonic inflammation and reduced monocyte infiltration into colonic tissues in Timd4 KO mice. Mechanistically, in vitro studies revealed that TIMD4 stabilized the LKB1-STRAD-MO25 complex via its intracellular domain, thereby activating the AMPK pathway and suppressing NF-κB-dependent chemokine production in macrophages. Based on these findings, we designed a TIMD4-derived peptide and developed a macrophage-targeted nanoparticle system (T4(365-378)‑NPs). Treatment with T4(365-378)-NPs reduced P65 phosphorylation and attenuated DSS-induced colitis in mice. Treatment with either T4(365-378)-NPs or the CCR2 antagonist attenuated DSS-induced colitis, and no statistically significant differences in the assessed outcomes were detected between the two groups. Administration of T4(365-378)-NPs before DSS exposure also attenuated subsequent colitis. Furthermore, combining the T4(365-378)‑NPs with anti-α4β7 or anti-TNF-α antibodies produced greater improvements than either monotherapy in the DSS-induced colitis model. These findings support further preclinical evaluation of TIMD4-derived peptide delivery as a potential therapeutic approach for intestinal inflammation.