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Published on: October 22, 2019
ADAM8 in macrophages exacerbates sepsis-induced cardiomyopathy by impeding efferocytosis
Zhenjun Ji1,2, Jiaqi Guo1, Mi Wang1
1Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China.
Introduction:
Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication characterized by acute cardiac dysfunction during sepsis., and macrophages play a crucial role in SICM pathogenesis. ADAM8 has been implicated in inflammation-driven diseases, yet its role in SICM remains uncharted.
Methods:
Mouse models of SICM were established using lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP). Macrophage-specific ADAM8 knockout (CKO) mice were generated. RNA transcriptome sequencing was conducted on left ventricular tissues sourced from ADAM8 CKO mice, as well as on RAW264.7 cell lines that were treated with both ADAM8 knockdown (KD) lentivirus and LPS.
Results:
Here, we demonstrate that ADAM8 expression is significantly upregulated in cardiac macrophages of SICM mice using single-cell transcriptomics and immunofluorescence. Macrophage-specific ADAM8 CKO mice exhibited preserved cardiac function, reduced myocardial injury markers, attenuated apoptosis (decreased Bax/Bcl2 ratio), and enhanced survival in both LPS-induced and CLP sepsis models. Transcriptomic analysis revealed downregulation of cytokine-cytokine receptor pathways in CKO hearts, suggesting diminished inflammatory responses. Mechanistically, ADAM8 deficiency promoted macrophage efferocytosis by increasing phagocytic receptors (MerTK) while reducing soluble Mer (sMer) generation. Conversely, sMer administration abolished the cardioprotective effects in CKO mice, exacerbating cardiac dysfunction and mortality.
Conclusions:
Our findings identify ADAM8 as a critical regulator of macrophage-mediated inflammation and impaired macrophage efferocytosis in SICM. Targeting ADAM8 or its downstream effectors may represent a novel therapeutic strategy for sepsis-induced cardiac complications.
Insights
ADAM8 in cardiac macrophages drives sepsis-induced cardiomyopathy by impairing efferocytosis. Blocking ADAM8 preserves heart function and improves survival in sepsis models, offering a new therapeutic target.
Area of Science:
- Cardiovascular Biology
- Immunology
- Sepsis Pathogenesis
Background:
- Sepsis-induced cardiomyopathy (SICM) is a severe complication of sepsis, characterized by cardiac dysfunction.
- Macrophages are key players in SICM, but the specific molecular mechanisms are not fully understood.
- ADAM8's role in inflammation-driven diseases is known, but its involvement in SICM is unexplored.
Purpose of the Study:
- To investigate the role of ADAM8 in the pathogenesis of sepsis-induced cardiomyopathy.
- To determine the impact of macrophage-specific ADAM8 deletion on cardiac function and survival during sepsis.
Main Methods:
- Established mouse models of SICM using LPS injection and cecal ligation and puncture (CLP).
- Generated macrophage-specific ADAM8 knockout (CKO) mice.
- Performed RNA transcriptome sequencing on cardiac tissues and macrophage cell lines.
Main Results:
- ADAM8 expression was significantly upregulated in cardiac macrophages during SICM.
- Macrophage-specific ADAM8 CKO mice showed preserved cardiac function, reduced injury, and enhanced survival.
- ADAM8 deficiency improved macrophage efferocytosis and reduced inflammatory pathways.
Conclusions:
- ADAM8 is a critical regulator of macrophage function in SICM.
- Targeting ADAM8 presents a potential therapeutic strategy for sepsis-induced cardiac complications.
