{
  "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.\n\nInflammatory 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.",
  "abstract_shown": true,
  "affiliations": [
    "Key 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.",
    "Department 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.",
    "The First School of Clinical Medicine, Shandong University, Jinan, Shandong, P. R. China.",
    "Department of Oral Medicine, Jining Medical University, Jining, Shandong, P. R. China.",
    "Department of Rheumatology, Fuding Hospital, Ningde City, Fujian Province, P. R. China.",
    "Key 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.",
    "Key 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.",
    "Institute of Pediatric Research, Children's Hospital Affiliated to Shandong University, Jinan, Shandong, P. R. China.",
    "Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P. R. China.",
    "Shandong 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."
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Huimin Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuzhen Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Ruiqing Yu"
    },
    {
      "affs": [
        0
      ],
      "name": "Kexin Liu"
    },
    {
      "affs": [
        2
      ],
      "name": "Dezhi Zheng"
    },
    {
      "affs": [
        0
      ],
      "name": "Bo Wang"
    },
    {
      "affs": [
        3
      ],
      "name": "Yuan Chang"
    },
    {
      "affs": [
        4
      ],
      "name": "Bing Liu"
    },
    {
      "affs": [
        5
      ],
      "name": "Xuetian Yue"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhuanchang Wu"
    },
    {
      "affs": [
        6
      ],
      "name": "Chunyang Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaohong Liang"
    },
    {
      "affs": [
        0
      ],
      "name": "Chunhong Ma"
    },
    {
      "affs": [
        7
      ],
      "name": "Guohua Liu"
    },
    {
      "affs": [
        1
      ],
      "name": "Jianhua Li"
    },
    {
      "affs": [
        8
      ],
      "name": "Leiqi Xu"
    },
    {
      "affs": [
        0,
        9
      ],
      "name": "Lifen Gao",
      "orcid": "0000-0003-2404-7439"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2kcsrwf4bpkwg.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pbio.3004056",
  "fulltext_url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004056",
  "id": "2kcsrwf4bpkwg",
  "issns": [
    "1545-7885",
    "1544-9173"
  ],
  "landing_url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004056",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1311|Inflammatory Bowel Disease"
    ],
    [
      "plos",
      "/Biology and life sciences/Anatomy/Digestive system/Gastrointestinal tract/Colon"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cell motility/Chemotaxis/Chemokines"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Macrophages"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Monocytes"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Macrophages"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Monocytes"
    ],
    [
      "plos",
      "/Biology and life sciences/Immunology/Immune cells/White blood cells/Macrophages"
    ],
    [
      "plos",
      "/Biology and life sciences/Immunology/Immune cells/White blood cells/Monocytes"
    ],
    [
      "plos",
      "/Medicine and health sciences/Anatomy/Digestive system/Gastrointestinal tract/Colon"
    ],
    [
      "plos",
      "/Medicine and health sciences/Gastroenterology and hepatology/Inflammatory bowel disease"
    ],
    [
      "plos",
      "/Medicine and health sciences/Gastroenterology and hepatology/Inflammatory bowel disease/Colitis"
    ],
    [
      "plos",
      "/Medicine and health sciences/Gastroenterology and hepatology/Inflammatory bowel disease/Colitis/Ulcerative colitis"
    ],
    [
      "plos",
      "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Macrophages"
    ],
    [
      "plos",
      "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Monocytes"
    ],
    [
      "plos",
      "/Research and analysis methods/Specimen preparation and treatment/Staining/Immunofluorescence staining"
    ]
  ],
  "openalex": "W7223108944",
  "pdf_url": "https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3004056&type=printable",
  "pmcid": "PMC13686490",
  "pmid": "42905753",
  "published": "2026-10-21",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/2kcsrwf4bpkwg.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:23Z",
      "native_id": "10.1371/journal.pbio.3004056",
      "source": "plos",
      "url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004056"
    },
    {
      "first_seen": "2026-10-30T12:19:53Z",
      "native_id": "MED:42905753",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42905753"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
    },
    {
      "field": "biology",
      "origin": "plos:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "A macrophage-targeted TIMD4 Peptide-Nanoparticle attenuates colitis symptoms and monocyte recruitment in a mouse model",
  "title_text": "A macrophage-targeted TIMD4 Peptide-Nanoparticle attenuates colitis symptoms and monocyte recruitment in a mouse model",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:53Z",
  "url": "https://research.draconitic.com/paper/2kcsrwf4bpkwg",
  "venue": "PLOS Biology",
  "versions": []
}