**3. Inflammasome activation: a central inflammatory driver of atherosclerosis**

Inflammasomes are intracellular immune sensors, which are tightly controlled. They assemble upon stimuli from tissue damage, infection or metabolic disturbances, and their activation results in production of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. There are several different inflammasomes, but the *NOD-like receptor containing a pyrin domain 3* (NLRP3) inflammasome is the most described and is an important constituent of innate immune apparatus. The NLRP3 inflammasome is a multimeric protein complex, which upon activation assembles and attracts caspase-1 molecules, which then is activated by self-cleavage. Active caspase-1 cleaves pro-IL⁻1β and pro-IL-18 to active cytokines ready for secretion [58, 59]. IL-1β is a prototypical proatherogenic cytokine, and NLRP3 is thus an important contributor to atherosclerotic inflammation. Cholesterol crystals, which deposit in atherosclerotic lesions, can activate the inflammasome both in vitro and in vivo [60, 61]. Further, the nonlipid danger signal ATP stimulates foam cell formation and cell migration through inflammasome activation [62]. Thus, the inflammasome promotes atherogenesis through inflammatory, as well as noninflammatory pathways, induced by lipid- as well as nonlipid stimuli. The NLRP3 inflammasome is present and activate in human atherosclerotic plaque [61]. Further, LDL receptor (LDLR)-deficient mice which received bone marrow from NLRP3-deficient mice show attenuated atherosclerosis, and silencing of NLRP3 in ApoE-deficient mice stabilizes atherosclerotic plaques, pointing to an important role in atherosclerotic disease development [60, 63].

epitopes (OSEs), an important class of DAMPs in atherosclerosis [65, 69]. Cholesterol saturation inside the plaques leads to the formation of cholesterol crystals, which are important activators of the NLRP3 inflammasome (see Section 3) [60]. Other crystal structures can also serve as DAMPs, such as monosodium urate (MSU) crystals, which are composed of crystalized uric acid that contributes to the increased risk of atherosclerosis in patients with gout [70]. Moreover, lipids, nucleic acids and proteins can be modified in the presence of sugars, forming advanced glycation end products (AGEs), which activate immune responses through specialized receptors. These DAMPs are especially prevalent in diabetic subjects, promoting atherosclerosis through vascular

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Necrotic cores of complex lesions are huge sources of inflammatory stimuli. In contrast to apoptosis, which is silent, necrosis and pyroptosis activate innate immune responses through the release of DAMPs such as heat shock proteins, nucleic acids, uric acid and ATP [65, 73, 74]. Further, as immune cells accumulate and the plaque develops, the demand for oxygen exceeds the availability, leading to hypoxic conditions. Hypoxia can activate the NLRP3 inflammasome and stimulate the polarization of M1 macrophages, causing increased inflammation in the plaques [75, 76]. Further, as mentioned, mechanical stress in the artery wall can also be a trigger of inflammation by stimulating endothelial activation, with subsequent activation of

The presence of risk factors provides continuous production of triggers, resulting in defective rescue mechanisms and persistent immune stimulation. Without relieve of these stimuli, a

Inflammation is a beneficial process; however, it becomes detrimental if the response is too strong or too long. Cessation of inflammation was previously thought of as a passive process; however, it is now known that resolution of inflammation is a highly active process, involving a complex network of mediators. For inflammation to stay homeostatic, these mechanisms need to be intact. Atherosclerosis is characterized by a chronic nonresolving low-grade inflammation. Thus, a defective resolution of inflammation is an important contributor to atherosclerotic development and sustainability. Resolution is driven by endogenous specialized lipid-derived mediators (SPMs), which are synthesized from fatty acids, as well as proteins such as IL-10, M1 macrophages and the nucleotides inosine and adenosine. These stimulate tissue repair and regeneration and can therefore be distinguished from the classical anti-inflammatory signals, which are merely antagonists of pro-inflammatory signals. In a normal immune response, the production of SPMs is initiated by the production of the pro-inflammatory prostaglandins. Defective resolution in atherosclerosis can be summarized in three processes: (1) sustained inflammation, (2) increased infiltration/reduced egress of immune cells and (3) defective efferocytosis. In early atherosclerotic plaques, the efferocytotic capacity of macrophages (ability to clear apoptotic cells) is sufficient. Thus, inflammatory cells are cleared from the lesion, and this process elicits the release of anti-inflammatory mediators that counteract the plaque development. In advanced plaques, the efferocytotic

nonresolving inflammation develops, which is a hallmark of atherogenesis.

dysfunction and increased inflammation [71, 72].

immune cells and VSMC in the artery wall.

**5. Defective resolution in atherosclerosis**
