Tissue-resident CCR2+ macrophage TREM-1/3 signaling is necessary for monocyte and neutrophil recruitment to injured hearts
Triggering receptor expressed on myeloid cells 1 (TREM-1) has been shown to amplify inflammatory signals, such as Toll-like receptor signaling, after infection and sterile injury. While previous studies have demonstrated that TREM-1 activation in circulating immune cells promotes injury, the role of TREM-1 signaling in tissue-resident cells in the context of sterile inflammation remains poorly understood. Here, we used a cardiac transplantation model to dissect how Trem1/3 expression on heart-resident cells regulates sterile inflammation. TREM-1 is expressed in heart-resident C-C chemokine receptor 2 (CCR2)<sup>+</sup> macrophages in mice and humans. TREM-1/3 signaling in tissue-resident CCR2<sup>+</sup> macrophages promotes C-C motif chemokine ligand 3 (CCL3) production and is critical for recruiting neutrophils and CCR2<sup>+</sup> monocytes after heart transplantation. We demonstrate prolonged allograft survival after transplantation of Trem1/3-deficient compared with wild-type hearts. We identify TREM-1/3 signaling in donor grafts as a potential future therapeutic target to blunt inflammation after myocardial ischemia-reperfusion injury.
Authors
- Jon H. Ritter (ORCID: https://orcid.org/0009-0003-4514-6935)
- Junedh Amrute (ORCID: https://orcid.org/0000-0002-6851-0168)
- Kory J. Lavine (ORCID: https://orcid.org/0000-0003-1948-9945)
- Hannah Luehmann (ORCID: https://orcid.org/0000-0002-7516-6772)
- Sumanth D. Prabhu (ORCID: https://orcid.org/0000-0002-7247-7241)
- Macee C. Owen
- Ruben G. Nava (ORCID: https://orcid.org/0000-0001-5685-9445)
- Marina Cella (ORCID: https://orcid.org/0000-0003-1230-1313)
- C. Liu (ORCID: https://orcid.org/0000-0001-8932-8835)
- Marco Colonna (ORCID: https://orcid.org/0000-0001-5222-4987)
- Daniel Kreisel (ORCID: https://orcid.org/0000-0002-7711-8651)
- Yuriko Terada (ORCID: https://orcid.org/0000-0003-1598-9360)
- Amit Bery (ORCID: https://orcid.org/0000-0002-1020-8839)
- Andrew L. Koenig (ORCID: https://orcid.org/0000-0003-4384-1267)
- Alexander N. Wein (ORCID: https://orcid.org/0000-0002-8813-3523)
- C. Corbin Frye (ORCID: https://orcid.org/0000-0002-4323-0696)
- Venkatrao Nunna
- Andrew E. Gelman (ORCID: https://orcid.org/0000-0002-0711-6343)
- Hao Dun (ORCID: https://orcid.org/0009-0004-9951-2854)
- Gyu Seong Heo (ORCID: https://orcid.org/0000-0001-6200-4742)
- Wenjun Li (ORCID: https://orcid.org/0000-0002-1923-5016)
- Yongjian Liu (ORCID: https://orcid.org/0000-0002-1118-1535)
Institutions
- Washington University in St. Louis (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115380
- Citations
- 7
- Primary Topic
- Inflammation biomarkers and pathways
- Type
- article
- Field-Weighted Citation Impact
- 5.58