Emerging evidence for beneficial macrophage functions in atherosclerosis and obesity-induced insulin resistance

Abstract

The discovery that obesity promotes macrophage accumulation in visceral fat led to the emergence of a new field of inquiry termed "immunometabolism". This broad field of study was founded on the premise that inflammation and the corresponding increase in macrophage number and activity was a pathologic feature of metabolic diseases. There is abundant data in both animal and human studies that supports this assertation. Established adverse effects of inflammation in visceral fat include decreased glucose and fatty acid uptake, inhibition of insulin signaling, and ectopic triglyceride accumulation. Likewise, in the atherosclerotic plaque, macrophage accumulation and activation results in plaque expansion and destabilization. Despite these facts, there is an accumulating body of evidence that macrophages also have beneficial functions in both atherosclerosis and visceral obesity. Potentially beneficial functions that are common to these different contexts include the regulation of efferocytosis, lipid buffering, and anti-inflammatory effects. Autophagy, the process by which cytoplasmic contents are delivered to the lysosome for degradation, is integral to many of these protective biologic functions. The macrophage utilizes autophagy as a molecular tool to maintain tissue integrity and homeostasis at baseline (e.g., bone growth) and in the face of ongoing metabolic insults (e.g., fasting, hypercholesterolemia, obesity). Herein, we highlight recent evidence demonstrating that abrogation of certain macrophage functions, in particular autophagy, exacerbates both atherosclerosis and obesity-induced insulin resistance. Insulin signaling through mammalian target of rapamycin (mTOR) is a crucial regulatory node that links nutrient availability to macrophage autophagic flux. A more precise understanding of the metabolic substrates and triggers for macrophage autophagy may allow therapeutic manipulation of this pathway. These observations underscore the complexity of the field "immunometabolism", validate its importance, and raise many fascinating and important questions for future study.

Keywords: Atherosclerosis; Autophagy; Cholesterol; Insulin resistance; Macrophage; Visceral adipose; mTOR.

Fig. 1

The spectrum of macrophage polarization. Although macrophage function has typically been dichotomized into classical (M1) or alternative (M2), recent data highlights the limitations of this classification and underscores the potential functional utility of “metabolically” (MMe) activated subsets [13, 14, 30]. Such a subset is characterized by proteins responsible for lipid uptake (CD36), storage (PLIN2), and export to high-density lipoproteins (ABCA1)

Fig. 2

Regulation of lipid metabolism in foam cells and tissue resident macrophages. (step 1, blue) In basal conditions, macrophages take up glucose to generate energy via oxidative metabolism, storing excess glucose in lipid droplets after de novo lipogenesis. (step 2, green) In fasting conditions, neutral lipases at the lipid droplet surface hydrolyze stored triglyceride (TG) to fatty acids (FA), which undergo beta-oxidation in adjacent mitochondria to generate adenosine triphosphate (ATP). (Step 3, red) In obesity or hypercholesterolemia, macrophages in the plaque or visceral adipose tissue may endocytose lipoproteins/lipid via scavenger receptors (CD36, SRA) or via micro pinocytosis. Engulfed lipoproteins are metabolized via lysosomal degradation. (step 4, black) Some stored lipid may also be metabolized via autophagy, which is initiated by formation of a phagophore. AMP activated protein kinase (AMPK) and mammalian target of rapamycin (mTORC1), respectively, activate and inhibit this process. The autophagosome fuses with the lysosome to generate the autolysosome. (step 5, orange) In the autolysosome lysosomal acid lipase (LAL) hydrolyzes cholesterol ester (CholE) to cholesterol (Chol). Whether or FA generated from the hydrolysis of CholE or TG are available for beta-oxidation is not yet known (not shown). However, the export of cholesterol is dependent on this process. The export of cholesterol is facilitated by the proteins of Niemann-Pick disease, type C1,2 (NPC1/2), and member 1 of human transporter subfamily ABCA (ABCA1). Depending upon the substrates within the autolysosome autophagy may be blocked at this step. This will result in the accumulation of sequestosome-1 (p62) and lipid in the autolysosome and prevent cholesterol efflux to high density lipoprotein (HDL). Decreased autophagic flux will also cause leakage of autolysosome contents into the cytoplasm (cathespins, reactive oxygen species) and cause activation of the inflammasome or unfolded protein response. These latter effects contribute to worsening of local inflammation or programmed cell death