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Global Translational Medicine Inflammation in CVD: Mechanisms and markers

1 cells, the predominant subset in plaques, release pro- IL-1β and pro-IL-18. 13,14 The subsequent activation phase
inflammatory cytokines, such as interferon-γ and tumor is triggered by stimuli characteristic of the atherogenic
necrosis factor-alpha (TNF-α), which amplify vascular environment, including extracellular cholesterol crystals,
inflammation, recruit additional immune cells, and oxidized LDL, potassium efflux, lysosomal destabilization,
destabilize plaques by promoting matrix degradation and and mitochondrial-derived reactive oxygen species. These
necrotic core expansion. signals converge to promote NLRP3 oligomerization and its
interaction with the adaptor protein apoptosis-associated
Meanwhile, B lymphocytes also play a pivotal speck-like protein containing a CARD (ASC) and pro-
role in the progression of ASCVD by amplifying caspase-1, forming the active inflammasome complex.
inflammatory responses within atherosclerotic Once assembled, this complex cleaves pro-caspase-1
plaques. Adaptive B2 cells contribute to disease into its active form, which subsequently processes pro-
pathogenesis by producing IgG antibodies against IL-1β and pro-IL-18 into their mature, secreted forms.
atherogenic antigens, which form immune complexes These cytokines propagate vascular inflammation by
and activate complement pathways, intensifying local inducing endothelial cell activation, upregulating adhesion
vascular inflammation. 11,12 These cells secrete pro- molecules, and recruiting monocytes to the arterial intima.
inflammatory cytokines, such as IL-6 and TNF-α, In vascular smooth muscle cells, inflammasome activity
further exacerbating endothelial dysfunction and promotes apoptosis and extracellular matrix degradation,
promoting plaque instability. By interacting with other while in macrophages, inflammasome-driven IL-1β release
immune cells and perpetuating inflammatory cascades, enhances foam cell formation and necrotic core expansion.
B lymphocytes contribute significantly to the chronic Together, these effects compromise fibrous cap integrity,
immune activation that drives the progression and reduce plaque stability, and increase susceptibility to
destabilization of atherosclerotic plaques in ASCVD. rupture and thrombosis.
The clonal expansion of T- and B-cells specific to The AIM2 inflammasome operates through a distinct
atherogenic antigens sustains the immune activation DNA-sensing mechanism, detecting cytoplasmic double-
within plaques, perpetuating a cycle of inflammation and stranded DNA (dsDNA) derived from mitochondrial
vascular injury. The accumulation of immune complexes, damage, necrotic cells, or neutrophil extracellular traps. 13,14
activation of complement pathways, and engagement On binding dsDNA, AIM2 undergoes conformational
+
of cytotoxic CD8 T cells further contribute to plaque changes that drive its oligomerization and subsequent
destabilization, emphasizing the multifaceted nature of recruitment of ASC and pro-caspase-1, leading to
active immunity in ASCVD. caspase-1 activation and downstream cytokine maturation.
In macrophages and endothelial cells, AIM2 activation
3. The role of inflammasomes in ASCVD has been shown to induce pyroptotic cell death through

3.1. Introduction to inflammasomes in ASCVD gasdermin D pore formation, disrupting membrane
integrity and releasing intracellular damage-associated
Inflammasomes are multiprotein complexes within the molecular patterns (DAMPs), such as DNA fragments,
cytoplasm that act as pivotal regulators of the inflammatory ATP, and oxidized lipids. 13,14 These DAMPs perpetuate
response. They link cellular stress and immune activation in local inflammation and act as secondary triggers for
the development and progression of ASCVD. The NLRP3 additional inflammasome activation, creating a self-
and absent in melanoma 2 (AIM2) inflammasomes are reinforcing inflammatory loop within the plaque. AIM2
the most extensively studied inflammasomes implicated has also been implicated in promoting plaque necrosis,
in ASCVD (Figure 3). Together, these inflammasomes expanding the necrotic core, and impairing resolution
destabilize atherosclerotic plaques, making them more pathways such as efferocytosis – further destabilizing
prone to rupture and thrombosis. the plaque microenvironment. The combined activity of
NLRP3 and AIM2 inflammasomes across multiple vascular
3.2. Mechanisms of NLRP3 and AIM2 cell types highlights their role as central orchestrators of
inflammasomes
atherosclerotic progression and potential therapeutic
The NLRP3 inflammasome is a central driver of targets for inflammation-driven CVD.
inflammation in atherosclerosis and is activated through
a well-characterized two-step process. The priming phase 3.3. The IL-1 cytokine signaling: Upstream initiator
is initiated by pattern recognition receptors, such as toll- of inflammation
like receptors, which activate NF-κB and upregulate the Before amplifying downstream mediators such as IL-6,
transcription of NLRP3 and its downstream effectors, pro- the IL-1 family – particularly IL-1α and IL-1β – initiates

Volume 4 Issue 3 (2025) 6 doi: 10.36922/GTM025100023