A macrophage-targeted TIMD4 Peptide-Nanoparticle attenuates colitis symptoms and monocyte recruitment in a mouse model
10 affiliations
- 1Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection Immunity and Disease Intervention of Shandong Province, and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P. R. China.
- 2Department of Biomaterials, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, P. R. China.
- 3The First School of Clinical Medicine, Shandong University, Jinan, Shandong, P. R. China.
- 4Department of Oral Medicine, Jining Medical University, Jining, Shandong, P. R. China.
- 5Department of Rheumatology, Fuding Hospital, Ningde City, Fujian Province, P. R. China.
- 6Key Laboratory for Experimental Teratology of Ministry of Education, Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P. R. China.
- 7Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P. R. China.
- 8Institute of Pediatric Research, Children's Hospital Affiliated to Shandong University, Jinan, Shandong, P. R. China.
- 9Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P. R. China.
- 10Shandong Key Laboratory of Oral Diseases & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P. R. China.
Abstract
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.
Inflammatory bowel disease is fueled by macrophage signals that recruit monocytes to the gut. This study shows that TIMD4 activates the AMPK pathway and suppresses NF-κB-dependent chemokine production in macrophages, and that a TIMD4 peptide nanoparticle alleviates these effects.
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BibTeX
@article{liu2026macrophagetargeted,
title = {{A macrophage-targeted TIMD4 Peptide-Nanoparticle attenuates colitis symptoms and monocyte recruitment in a mouse model}},
author = {Huimin Liu and Yuzhen Wang and Ruiqing Yu and Kexin Liu and Dezhi Zheng and Bo Wang and Yuan Chang and Bing Liu and Xuetian Yue and Zhuanchang Wu and Chunyang Li and Xiaohong Liang and Chunhong Ma and Guohua Liu and Jianhua Li and Leiqi Xu and Lifen Gao},
journal = {PLOS Biology},
year = {2026},
month = oct,
doi = {10.1371/journal.pbio.3004056},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004056},
note = {CC BY},
}
RIS
TY - JOUR
TI - A macrophage-targeted TIMD4 Peptide-Nanoparticle attenuates colitis symptoms and monocyte recruitment in a mouse model
AU - Huimin Liu
AU - Yuzhen Wang
AU - Ruiqing Yu
AU - Kexin Liu
AU - Dezhi Zheng
AU - Bo Wang
AU - Yuan Chang
AU - Bing Liu
AU - Xuetian Yue
AU - Zhuanchang Wu
AU - Chunyang Li
AU - Xiaohong Liang
AU - Chunhong Ma
AU - Guohua Liu
AU - Jianhua Li
AU - Leiqi Xu
AU - Lifen Gao
PY - 2026
DA - 2026/10/21
JO - PLOS Biology
DO - 10.1371/journal.pbio.3004056
UR - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004056
AB - 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. Inflammatory bowel disease is fueled by macrophage signals that recruit monocytes to the gut. This study shows that TIMD4 activates the AMPK pathway and suppresses NF-κB-dependent chemokine production in macrophages, and that a TIMD4 peptide nanoparticle alleviates these effects.
SN - 1545-7885
SN - 1544-9173
ER -