**4. Danger signals in atherosclerosis**

Inflammation is a part of the body's response to harm, either from microbes, such as virus and bacteria, from burns or toxins, or from injury. The main function is to eliminate the insult, remove damaged tissue and restore tissue homeostasis. In atherosclerosis, the signals of harm, termed *triggers*, are numerous. In contrast to infectious disease, the most typical triggers in atherogenesis are however sterile. These are termed damage-associated molecular patterns (DAMPs) and are host-derived danger signals released upon tissue damage, metabolic disturbances, or environmental stress. The risk factors of CVD include hyperlipidemia, smoking, hypertension and hyperglycemia, and all these factors cause DAMPs. There is, however, also evidence supporting a role for pathogens in atherosclerosis. These are termed pathogen-associated molecular patterns (PAMPs). Bacterial and viral microbes are found in atherosclerotic plaques and are associated with disease risk [64, 65]. In addition to pathogens, gut microbiota is a potential source of PAMPs, also linked to atherogenesis [66]. The causal relationship between the endogenous DAMPs and atherosclerosis is stronger than for PAMPs. Microbes do not seem to be required for atherogenesis, as germ-free mice are not protected against disease [67]. The DAMPs comprehend the necessary evil of atherogenesis, namely lipids. As mentioned, the interaction between lipids and immune activation is the hallmark of atherosclerotic disease. Nonmodified fatty acids can activate immune responses, and while saturated fats are shown to stimulate inflammation, polyunsaturated fats are repressors [68]. It is, however, the modified lipids that are the typical triggers during atherogenesis. In hyperlipidemia, LDL undergoes oxidation, forming oxidation-specific 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 dysfunction and increased inflammation [71, 72].

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 immune cells and VSMC in the artery wall.

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 nonresolving inflammation develops, which is a hallmark of atherogenesis.
