Targeting Macrophage-Mediated Mechanisms in Sepsis-Induced Cardiomyopathy: From Pathophysiology to Therapeutic Strategies

Figures

• 

  Figure 1. Optogenetic regulation of macrophage inflammatory response via the cAMP-PKA signaling pathway. Blue light (λ = 460 ± 10 nm) activates photoactivated adenylyl cyclase (bPAC) transfected into macrophages, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP). Elevated cAMP activates protein kinase A (PKA), which subsequently suppresses the NF-κB signaling pathway, thereby reducing the expression of pro-inflammatory cytokines such as TNF-α and IL-1β. This optogenetic approach offers a precise spatiotemporal strategy to modulate macrophage-mediated inflammation in sepsis-induced cardiomyopathy (SICM).

• 

  Figure 2. Mechanisms of inflammasome activation in macrophages. Different pathogen-associated molecular patterns (PAMPs) and danger signals activate specific inflammasome sensors. Lysosomal rupture, potassium ion efflux and ROS burst triggers the NLRP3 inflammasome. Cytosolic dsDNA is sensed by AIM2. Bacterial toxins activate the PYRIN inflammasome, while flagellin is recognized by NLRC4. NLRP3. AIM2 and PYRIN sensors recruit the adaptor protein ASC, while NLRC4 sensors recruit the adaptor protein NARP, leading to caspase-1 activation. Caspase-1 cleaves Gasdermin D (GSDMD), inducing pore formation and macrophage pyroptosis, accompanied by the release of IL-18 and IL-1β. The domain structure of pro-caspase-1 and its active form (Caspase-1, p20/p10) is shown.

• 

  Figure 3. Pro-inflammatory role of M1 macrophages in cardiac injury and remodeling. Upon stimulation with LPS and IFN-γ, macrophages polarize into the M1 phenotype, leading to NF-κB activation. Activated NF-κB drives the production of TNF-α and IL-1β, which impair myocardial contractility by suppressing calcium (Ca2⁺) influx. Concurrently, NF-κB activation promotes ROS generation and iNOS expression, which attenuate myocardial contractility through inhibition of ADP/ATP metabolism. M1 macrophages also secrete exosomes containing miR-155, which are transferred into cardiomyocytes to activate the p38-MAPK–NLRP3 axis and promote pyroptosis. In parallel, M1 macrophage-derived MMP-9 exerts multifaceted detrimental effects: it cleaves and activates pro-inflammatory factors and chemokines into bioactive matrix fragments, thereby recruiting immune cells and promoting infiltration; it degrades connexin-43 expression, triggering arrhythmia; it degrades type I and III collagen fibers, leading to adverse ventricular remodeling; it decreases structural proteins, resulting in impaired myocardial contractility; and it degrades type IV collagen fibers, tight junction proteins, and laminin, causing severe…

• 

  Figure 4. Neuro-immune crosstalk in cardiac inflammation. Pro-inflammatory cytokines such as IL-1 act on central nervous system regions including the subfornical organ (SFO) and paraventricular nucleus (PVN), modulating autonomic outflow. Sympathetic activation promotes MAPK and NF-κB pathways, enhancing TNF-α and IL-1 production. Excessive inflammation leads to overproduction of iNOS/NO, which disrupts calcium homeostasis and suppresses cardiac contractility. Parasympathetic activity may exert anti-inflammatory effects, highlighting bidirectional neuro-immune interactions in cardiovascular pathology.

• 

  Figure 5. Protective and fibrotic roles of M2 macrophages in myocardial repair. In the early stage after injury, M2 macrophages exhibit anti-inflammatory properties and promote tissue repair. However, persistent M2 activation, driven by IL-4/IL-13, can lead to excessive collagen deposition (type I and III fibers), resulting in myocardial fibrosis and adverse structural remodeling.