Inflammation, immunity, and cardiovascular diseases
image: Cardiovascular stress signals (e.g., hemodynamic shear, oxidized lipids, and ischemia) act on endothelial and immune cells to activate and amplify inflammation through NF-κB, the NLRP3 inflammasome, and JAK/STAT signaling, inducing proinflammatory cytokines/chemokines (IL-6, IL-1β, TNF-α, and CCL2) and self-amplifying circuits; clinically, inflammatory burden is reflected by biomarkers such as hs-CRP, IL-6, and Lp-PLA2. In parallel, immune cells undergo metabolic remodeling (e.g., glucose flux through glycolysis to pyruvate/lactate vs. OXPHOS and fatty-acid oxidation), which tunes immune function and cell-fate decisions and contributes to atherosclerotic plaque instability. Cellular stress triggers regulated death modalities (apoptosis, autophagy, and ferroptosis), releasing DAMPs (e.g., ATP, HMGB1, and mtDNA) that reshape the cytokine/DAMP milieu and further modulate immunity between effector/proinflammatory programs (e.g., M1 macrophages, ROS, and Th1/Th17) and resolution/repair programs (e.g., M2 macrophages, Tregs, and IL-10). Together, these interconnected processes culminate in myocardial remodeling and injury, highlighting the IICM systems perspective as a foundation for CVD precision medicine.
Credit: Dezhi Guo and Wangzheqi Zhang
Cardiovascular diseases (CVDs) continue to be the number one cause of morbidity and mortality worldwide, but therapeutic interventions aimed at targeting individual inflammatory mediators exhibit inconsistent and context-dependent benefits, highlighting limitations associated with pathway-focused intervention strategies. Emerging data suggest that inflammation and immunity in CVDs function not as isolated processes but rather as a dynamic regulatory system of interconnected networks that link inflammatory signaling to the state of immune cells, programmed cell death, and metabolic reprogramming. Pro-inflammatory cytokines and chemokines engage self-amplifying immune circuits promoting atherosclerotic plaque instability and myocardial remodeling, whereas counter-regulatory immune programs are indispensable for resolution, tissue repair, and re-establishment of homeostasis. Regulated cell death modes, such as apoptosis, necroptosis, and ferroptosis, along with immunometabolic reprogramming importantly shape disease trajectories by intertwining cellular stress responses with immune activity/inflammatory resolution. From a network perspective, CVD is governed by context- and time-dependent immune network states instead of a linear series of signaling events. In this review, we integrate molecular–cellular and clinical evidence to delineate the organizing principles of the inflammation–immunity network, and establish a conceptual framework for the organization of this network in CVDs that accounts for diverse therapeutic responses and guides biomarker-driven, precision immunomodulatory interventions.