The article discusses the relationship between cholesterol accumulation in macrophages and other immune cells and inflammatory responses, particularly in the context of atherosclerosis and other metabolic diseases. Hypercholesterolemia leads to cholesterol accumulation, which activates Toll-like receptors (TLRs) and inflammasomes, promoting inflammation. However, cholesterol accumulation also activates liver X receptors (LXRs), which counter-regulate the inflammatory response by upregulating cholesterol efflux via ATP-binding cassette transporters (ABCA1 and ABCG1). This process, known as reverse cholesterol transport (RCT), helps to reduce cholesterol levels and inflammation. The acute phase response, induced by infections or inflammation, can inhibit RCT by suppressing the expression of genes involved in cholesterol efflux and promoting the production of pro-inflammatory mediators. In contrast, cholesterol accumulation in macrophages can lead to the formation of cholesterol crystals, which activate the NLRP3 inflammasome and promote further inflammation. The article also highlights the role of 25-hydroxycholesterol in suppressing inflammasome activation and its potential therapeutic applications. Finally, it discusses the importance of increased bone marrow myelopoiesis and extramedullary hematopoiesis in the production of inflammatory cells, and the potential of targeting cholesterol and inflammation as therapeutic strategies for conditions such as atherosclerosis, obesity, and autoimmune diseases.The article discusses the relationship between cholesterol accumulation in macrophages and other immune cells and inflammatory responses, particularly in the context of atherosclerosis and other metabolic diseases. Hypercholesterolemia leads to cholesterol accumulation, which activates Toll-like receptors (TLRs) and inflammasomes, promoting inflammation. However, cholesterol accumulation also activates liver X receptors (LXRs), which counter-regulate the inflammatory response by upregulating cholesterol efflux via ATP-binding cassette transporters (ABCA1 and ABCG1). This process, known as reverse cholesterol transport (RCT), helps to reduce cholesterol levels and inflammation. The acute phase response, induced by infections or inflammation, can inhibit RCT by suppressing the expression of genes involved in cholesterol efflux and promoting the production of pro-inflammatory mediators. In contrast, cholesterol accumulation in macrophages can lead to the formation of cholesterol crystals, which activate the NLRP3 inflammasome and promote further inflammation. The article also highlights the role of 25-hydroxycholesterol in suppressing inflammasome activation and its potential therapeutic applications. Finally, it discusses the importance of increased bone marrow myelopoiesis and extramedullary hematopoiesis in the production of inflammatory cells, and the potential of targeting cholesterol and inflammation as therapeutic strategies for conditions such as atherosclerosis, obesity, and autoimmune diseases.