Cholesterol accumulation in macrophages and immune cells promotes inflammation by enhancing Toll-like receptor (TLR) signaling, inflammasome activation, and the production of monocytes and neutrophils. While cholesterol accumulation may have beneficial effects in fighting infections, it worsens chronic metabolic diseases like atherosclerosis and obesity. Therapies such as increasing high-density lipoprotein (HDL) levels can reduce inflammation and benefit patients with metabolic diseases. In industrialized societies, high-fat, high-cholesterol diets (Western-type diets) lead to hypercholesterolaemia and atherosclerosis, especially in genetically predisposed individuals. Low-density lipoprotein (LDL) promotes cholesterol accumulation in the arterial wall, driving atherosclerosis. High-density lipoprotein (HDL) opposes this by promoting cholesterol efflux and reducing inflammation. Modified LDL functions as a ligand for macrophage pattern recognition receptors, triggering pro-inflammatory signaling pathways and causing cellular cholesterol accumulation, which amplifies TLR signaling. Counter-regulatory mechanisms, such as the liver X receptor (LXR)-retinoid X receptor (RXR) heterodimer, counteract cholesterol accumulation by promoting cholesterol efflux via ABC transporters. However, TLR activation suppresses LXR activity, leading to decreased cholesterol efflux and amplified TLR signaling. The acute phase response inhibits reverse cholesterol transport (RCT), which may be beneficial in immune responses but harmful in chronic diseases. Cholesterol accumulation in macrophages can lead to TLR signaling, inflammasome activation, and atherosclerosis. Inflammatory responses can be counteracted by HDL, which promotes cholesterol efflux and reduces inflammation. However, during acute infections, HDL can become dysfunctional and pro-inflammatory. Cholesterol efflux pathways suppress TLR signaling and inflammatory cytokine expression in atherosclerotic plaques. Cholesterol accumulation in macrophages can lead to TLR signaling, inflammasome activation, and atherosclerosis. Inflammasome activation requires two signals: a priming signal from TLR activation and a second signal from cholesterol crystals. Inflammasome activation leads to the secretion of pro-inflammatory cytokines like IL-1β and IL-18. Cholesterol crystals and minimally oxidized LDL can induce inflammasome activation in macrophages, contributing to atherosclerosis. 25-hydroxycholesterol (25-OH cholesterol) has anti-inflammatory effects by suppressing inflammasome activation. Cholesterol 25-hydroxylase-deficient mice show increased sensitivity to septic shock but stronger bacterial growth suppression. 25-OH cholesterol suppresses cholesterol biosynthetic genes by inhibiting SREBP2 cleavage. LXR activation promotes cholesterol efflux, fatty acid elongation, and anti-inflammatory effects. LXRs also enhance efferocytosis, reducing TLR4-mediated inflammatory responses. LXRs areCholesterol accumulation in macrophages and immune cells promotes inflammation by enhancing Toll-like receptor (TLR) signaling, inflammasome activation, and the production of monocytes and neutrophils. While cholesterol accumulation may have beneficial effects in fighting infections, it worsens chronic metabolic diseases like atherosclerosis and obesity. Therapies such as increasing high-density lipoprotein (HDL) levels can reduce inflammation and benefit patients with metabolic diseases. In industrialized societies, high-fat, high-cholesterol diets (Western-type diets) lead to hypercholesterolaemia and atherosclerosis, especially in genetically predisposed individuals. Low-density lipoprotein (LDL) promotes cholesterol accumulation in the arterial wall, driving atherosclerosis. High-density lipoprotein (HDL) opposes this by promoting cholesterol efflux and reducing inflammation. Modified LDL functions as a ligand for macrophage pattern recognition receptors, triggering pro-inflammatory signaling pathways and causing cellular cholesterol accumulation, which amplifies TLR signaling. Counter-regulatory mechanisms, such as the liver X receptor (LXR)-retinoid X receptor (RXR) heterodimer, counteract cholesterol accumulation by promoting cholesterol efflux via ABC transporters. However, TLR activation suppresses LXR activity, leading to decreased cholesterol efflux and amplified TLR signaling. The acute phase response inhibits reverse cholesterol transport (RCT), which may be beneficial in immune responses but harmful in chronic diseases. Cholesterol accumulation in macrophages can lead to TLR signaling, inflammasome activation, and atherosclerosis. Inflammatory responses can be counteracted by HDL, which promotes cholesterol efflux and reduces inflammation. However, during acute infections, HDL can become dysfunctional and pro-inflammatory. Cholesterol efflux pathways suppress TLR signaling and inflammatory cytokine expression in atherosclerotic plaques. Cholesterol accumulation in macrophages can lead to TLR signaling, inflammasome activation, and atherosclerosis. Inflammasome activation requires two signals: a priming signal from TLR activation and a second signal from cholesterol crystals. Inflammasome activation leads to the secretion of pro-inflammatory cytokines like IL-1β and IL-18. Cholesterol crystals and minimally oxidized LDL can induce inflammasome activation in macrophages, contributing to atherosclerosis. 25-hydroxycholesterol (25-OH cholesterol) has anti-inflammatory effects by suppressing inflammasome activation. Cholesterol 25-hydroxylase-deficient mice show increased sensitivity to septic shock but stronger bacterial growth suppression. 25-OH cholesterol suppresses cholesterol biosynthetic genes by inhibiting SREBP2 cleavage. LXR activation promotes cholesterol efflux, fatty acid elongation, and anti-inflammatory effects. LXRs also enhance efferocytosis, reducing TLR4-mediated inflammatory responses. LXRs are