A New Frontier in Immunometabolism. Cholesterol in Lung Health and Disease

Abstract

The lung has a unique relationship to cholesterol that is shaped by its singular physiology. On the one hand, the lungs receive the full cardiac output and have a predominant dependence on plasma lipoprotein uptake for their cholesterol supply. On the other hand, surfactant lipids, including cholesterol, are continually susceptible to oxidation owing to direct environmental exposure and must be cleared or recycled because of the very narrow biophysical mandates placed upon surfactant lipid composition. Interestingly, increased lipid-laden macrophage "foam cells" have been noted in a wide range of human lung pathologies. This suggests that lipid dysregulation may be a unifying and perhaps contributory event in chronic lung disease pathogenesis. Recent studies have shown that perturbations in intracellular cholesterol trafficking critically modify the immune response of macrophages and other cells. This minireview discusses literature that has begun to demonstrate the importance of regulated cholesterol traffic through the lung to pulmonary immunity, inflammation, and fibrosis. This emerging recognition of coupling between immunity and lipid homeostasis in the lung presents potentially transformative concepts for understanding lung disease and may also offer novel and exciting avenues for therapeutic development.

Keywords: innate immunity; lipoproteins; liver X receptors; oxysterols.

Figure 1.

Reverse cholesterol transport pathway. Reverse cholesterol transport is the pathway by which tissue macrophages avoid toxic cholesterol overload. Cellular uptake of cholesterol from low-density lipoprotein (LDL) particles or oxidized LDL (oxLDL) particles via the LDL receptor (LDLR) or scavenger receptors (SRs), respectively, inhibits sterol response element–binding protein 2 (SREBP2) and activates liver X receptors (LXRs). The LXRs promote compensatory cholesterol efflux by upregulating ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1, respectively). ABCA1 and ABCG1 together increase mobilization of cellular cholesterol to high-density lipoprotein (HDL) particles in the extracellular space. Plasma HDL delivers cholesterol to hepatocytes, where it is internalized via scavenger receptor BI (SR-BI). Cholesterol cleared from the plasma is then exported to the biliary system and from there to the intestinal lumen, where it can be excreted from the host. Apo B100 = apolipoprotein B 100; ApoA-1 = apolipoprotein A-I.

Figure 2.

Interactions between cholesterol and proinflammatory Toll-like receptor 4 (TLR4) signaling in the macrophage. Oxysterols accumulate upon cholesterol internalization by the macrophage, activating liver X receptor (LXR). LXR up-regulates the cholesterol efflux proteins ATP-binding cassette A1 and G1 (ABCA1 and ABCG1, respectively) and inhibits proinflammatory cytokine induction by suppressing the activity of transcription factors (i.e., nuclear factor-κB [NF-κB], activator protein [AP]-1, and signal transducer and activator of transcription [STAT]-1) at gene promoters. ABCA1 and ABCG1 inhibit TLR4 activation in the plasma membrane through reducing lipid raft cholesterol (through promoting cholesterol efflux to the extracellular acceptors apolipoprotein A-I [ApoA-I] and high-density lipoprotein [HDL], respectively). HDL also directly suppresses lipopolysaccharide (LPS) signaling by binding and neutralizing LPS.