The immunometabolic axis of sepsis-related myocardial injury: macrophage reprogramming as a central mechanism and therapeutic target

Figures

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  Figure 1. The immunometabolic axis of macrophages in sepsis-related myocardial injury. This schematic illustrates the central, integrative hypothesis of this review. Sepsis (cause) drives profound metabolic reprogramming in cardiac macrophages, characterized by a shift toward aerobic glycolysis in pro-inflammatory states and oxidative metabolism in reparative states. This reprogramming serves as the central mechanism that, through the release of specific cytokines, metabolites, reactive species, and extracellular vesicles, simultaneously engages five core pathophysiological pillars of SRMI: inflammatory activation, calcium dyshomeostasis, oxidative stress, mitochondrial dysfunction, and metabolic dysregulation. For each pillar, the figure delineates the key macrophage-derived effector. The convergence of these parallel yet interconnected pathways culminates in the outcome of myocardial contractile dysfunction and hemodynamic instability. AMPK, AMP-activated Protein Kinase; ATP, Adenosine Triphosphate; CPT1, Carnitine Palmitoyltransferase1; EVs, Extracellular Vesicles; FAO, Fatty Acid Oxidation; GLUT1, Glucose Transporter 1; HIF-1α, Hypoxia-Inducible Factor 1-alpha; HK2, Hexokinase 2;…

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  Figure 2. Heterogeneity and polarization dynamics of cardiac macrophages in sepsis. (A) Heterogeneity of cardiac macrophage populations in sepsis, as categorized based on markers and functions described in published single-cell transcriptomic studies. The cellular mechanism underlying the cardiac immune response to sepsis (cause) is the expansion of a heterogeneous macrophage landscape. This panel classifies major subsets (e.g., resident TREM2hi, infiltrating CCR2+, and novel post-sepsis clusters) that emerge, each associated with specific functional phenotypes. (B) The polarization mechanism determines functional fate. External signals (cause: e.g., PAMPs like LPS vs. cytokines like IL-4) activate intracellular pathways that mechanistically drive naïve or recruited macrophages toward pro-inflammatory (M1) or anti-inflammatory/reparative (M2) phenotypes. This dynamic switch critically influences the tissue outcome, balancing between inflammatory injury and healing. Arg1, Arginase 1; CCL, C-C Motif Chemokine Ligand; CCR2, C-C Motif Chemokine Receptor 2; FAO, Fatty Acid Oxidation; HLA-DR, Human Leukocyte Antigen DR; HMGB1, High Mobility Group Box 1; IFN-γ, Interferon-gamma; IL, Interleukin;…

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  Figure 3. Metabolic reprogramming underpinning macrophage M1 and M2 polarization. This figure contrasts the specific metabolic mechanisms that enact macrophage polarization. Distinct stimuli (cause) trigger a mechanistic rewiring of core pathways: inflammatory signals promote aerobic glycolysis and a broken TCA cycle in M1 cells, while anti-inflammatory signals enhance oxidative phosphorylation and fatty acid oxidation in M2 cells. These divergent metabolic programs directly power and define their respective pro-inflammatory or anti-inflammatory/reparative functional phenotypes. AMPK, AMP-activated Protein Kinase; ADP, Adenosine Diphosphate; ATP, Adenosine Triphosphate; α-KG, α-Ketoglutaric Acid; CPT1, Carnitine Palmitoyltransferase1; FADH2, Flavine Adenine Dinucleotide, Reduced; FAO, Fatty Acid Oxidation; FFA, Free Fat Acid; GABA, Gama-Aminobutyric Acid; GLUT1, Glucose Transporter 1; HIF-1α, Hypoxia-Inducible Factor 1-alpha; IFN-γ, Interferon-gamma; IL, Interleukin; iNOS, Inducible Nitric Oxide Synthase; JAK, Janus Kinase; LPS, Lipopolysaccharide; NADH, Nicotinamide Adenine Dinucleotide; NADPH, Nicotinamide Adenine Dinucleotide Phosphate Oxidase; NF-κB, Nuclear Factor…

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  Figure 4. Therapeutic strategies targeting macrophage metabolic reprogramming in sepsis-related myocardial injury. This overview categorizes interventions based on their action within a therapeutic logic model. The cause (therapeutic intervention) is designed to mechanistically modulate specific nodes in macrophage metabolism (e.g., via small molecules, nucleic acids, or biologics). This precise targeting aims to shift the macrophage phenotype from a detrimental M1 state toward a protective M2 state. The intended outcome of these strategies is the attenuation of myocardial injury and the improvement of cardiac function in sepsis. 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; 4-OI, 4-octyl-itaconate-lonidamine disulfide; AMPK, AMP-activated Protein Kinase; CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; Cxcl2, C-X-C Motif Chemokine Ligand 2; EVs, Extracellular Vesicles; GSK-3β, Glycogen Synthase Kinase-3β; HK2, Hexokinase 2; HMGB1, High Mobility Group Box 1; KLF14, Kruppel-like Factor 14; LNP, Lipid Nanoparticle; LILRA5, Leukocyte Immunoglobulin-Like Receptor Subfamily A Member 5; miR, micro RNA; MT, Mitochondrion; NF-κB, Nuclear Factor Kappa-Light-Chain-Enhancer of…