Key result
Resident CLEC4E deletion reduces 28-day infarct size by ~13 percentage points vs immune cell deletion.
Why the study?
The c-type lectin receptor CLEC4E is expressed on both infiltrating immune cells and tissue resident cells, leaving it unclear which cellular compartment mediates cardioprotection when CLEC4E signaling is inhibited during myocardial ischemia-reperfusion injury.
Does selective deletion of CLEC4E in cardiac resident cells compared to infiltrating bone marrow-derived immune cells reduce infarct size and improve left ventricular remodeling in a mouse model of myocardial ischemia-reperfusion injury?
Does selective deletion of CLEC4E in cardiac resident cells compared to infiltrating bone marrow-derived immune cells reduce infarct size and improve left ventricular remodeling in a mouse model of myocardial ischemia-reperfusion injury?
In a murine ischemia-reperfusion model, deletion of CLEC4E specifically in cardiac resident cells rather than infiltrating bone marrow-derived immune cells reduces 28-day infarct size and preserves left ventricular systolic function, identifying cardiac-resident CLEC4E as a potential therapeutic target.
CLEC4E in cardiac resident cells may drive adverse remodeling; leaves open selective inhibition as a therapeutic strategy.
The c-type lectin receptor CLEC4E plays a critical role in innate immune responses to ischemic tissue damage, and is expressed on infiltrating immune cells and tissue resident cells. We investigated whether inhibition of CLEC4E signaling in resident cells or infiltrating immune cells, mediates cardioprotection in myocardial ischemia-reperfusion (I/R) injury, and explored associated molecular pathways. Methods: We generated chimeric mice via sublethal total body irradiation followed by adoptive transfer of WT C57Bl6/J bone marrow cells (BMCs) in CLEC4E −/− mice and CLEC4E −/− BMCs in WT mice (n = 86). Four weeks after BMC transfer, we induced I/R injury by 30 min LAD occlusion. Myocardial necrosis was measured using troponin I (TnI) at 90 min; infarct size and LV remodeling were assessed by gadolinium-enhanced MRI at 24 h and 28 d. Hearts and bones were harvested at 28 d for immunohistochemistry, Olink-based myocardial proteomic analysis, and genotyping. Results: BMC analysis confirmed successful CLEC4E chimerism after transfer of CLEC4E −/− vs. WT progenitors. TnI levels and infarct size at 24 h were similar in both groups, but at 28 d, CLEC4E −/− mice with WT BMCs (n = 26) showed better LV function (LVEF 62% vs. 47%, p < 0.05) and smaller infarcts (6.9% vs. 19.8% LVmass, p < 0.01) than WT with CLEC4E −/− BMCs (n = 22). Proteomic analysis revealed enhanced pro-inflammatory and pro-fibrotic protein expression in WT with CLEC4E −/− BMCs. Conclusion: Deletion of CLEC4E in non–bone marrow–derived cardiac resident cells confers cardioprotection post-I/R. Targeting CLEC4E signaling and its downstream effectors in cardiac tissue may offer a novel therapeutic strategy for I/R injury.
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Algoet et al. (2026) studied Myocardial ischemia-reperfusion injury (n=86). CLEC4E deletion in cardiac resident cells (CLEC4E−/− mice transplanted with WT bone marrow) vs. CLEC4E deletion in infiltrating immune cells (WT mice transplanted with CLEC4E−/− bone marrow) was evaluated on Infarct size (% of left ventricular mass) at 28 days (p=<0.01). CLEC4E deletion in cardiac resident cells reduced 28-day infarct size (6.9% vs. 19.8% LV mass, p < 0.01) and improved LVEF (62% vs. 47%, p < 0.05) compared to immune cell deletion.
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