Cholesterol, inflammation and innate immunity

Abstract

Reverse cholesterol transport is a process by which cholesterol is transferred from peripheral cells, including macrophages, to the liver for excretion. The acute phase response results in suppression of reverse cholesterol transport at multiple steps, which may in turn promote cholesterol accumulation in macrophages and other immune cells. This can lead to a beneficial enhancement of inflammatory responses in the setting of infection, but when inflammation becomes prolonged these changes may worsen conditions such as atherosclerosis and obesity. During the acute phase response, high-density lipoprotein (HDL) levels are decreased and compositional changes in HDL, including myeloperoxidase-mediated modifications of apolipoprotein A1 (APOA1), may convert HDL into a dysfunctional form that cannot efficiently mediate cholesterol efflux and that becomes pro-inflammatory. Although these changes in HDL and APOA1 are probably pro-atherogenic, they may also have a physiological function in the setting of infection by enhancing the inflammatory response. Liver X receptor (LXR) transcription factors promote reverse cholesterol transport by inducing the expression of genes involved in cellular cholesterol efflux, transport in the bloodstream and excretion in the liver. The mechanisms connecting inflammation with decreases in reverse cholesterol transport include the ability of endotoxins to suppress the expression of LXR and its partner retinoid X recceptor (RXR), as well as the suppression of cellular LXR responses via a trans-repression mechanism. The mechanisms of pro-inflammatory effects of cellular cholesterol accumulation include enhanced Toll-like receptor (TLR) signalling and inflammasome activation. Inflammasome activation may be stimulated by cholesterol crystal uptake or formation in macrophages. Conversely, the induction of cholesterol 25-hydroxylase by lipopolysaccharide and type I interferons opposes inflammasome activation, probably because 25-hydroxycholesterol suppresses cellular sterol synthesis. Defective cholesterol efflux promotes monocyte and neutrophil production in the bone marrow and the spleen, involving the proliferation of haematopoietic stem cells (HSCs) and myeloid progenitor cells, mobilization of HSCs and extramedullary haematopoiesis. Although these pathways probably enhance the response to infections, genetic suppression and dietary challenge lead to aberrant responses that promote atherogenesis. Therapeutic interventions such as increased production or infusion of HDL may sever the links between cholesterol accumulation and inflammation with benefits for metabolic diseases. This may involve infusions of cholesterol-poor reconstituted HDL or targeting the APOA1 gene locus to increase endogenous APOA1 production.