Alternative macrophage activation and metabolism

Abstract

Obesity and its attendant metabolic disorders represent the great public health challenge of our time. Recent evidence suggests that onset of inflammation in metabolic tissues pathogenically links obesity to insulin resistance and type 2 diabetes. In this review, we briefly summarize the extant literature, paying special attention to the central role of the tissue-associated macrophage in the initiation of metabolic inflammation. We argue that rather than representing simple inflammatory disease, obesity and metabolic syndrome represent derangements in macrophage activation with concomitant loss of metabolic coordination. As such, the sequelae of obesity are as much products of the loss of positive macrophage influences as they are of the presence of deleterious inflammation. The therapeutic implications of this conclusion are profound because they suggest that pharmacologic targeting of macrophage activation, rather than simply inflammation, might be efficacious in treating this global epidemic.

Figure 1. Classical and alternative macrophage activation

Macrophage activation comprises a broad spectrum of activities coordinated in response to specific environmental stimuli. While in reality a continuum, these responses can be separated into two basic patterns: classical, or M1, and alternative, or M2. a) Classical activation is a pro-inflammatory state purposed for the rapid destruction of bacterial invaders. Classically activated macrophages generate induce reactive oxygen species (ROS) and nitric oxide (NO) for their microbicidal actions, and secrete pro-inflammatory cytokines, such as TNFα and IL-12, to enhance cell mediated immunity. b) In contrast, alternative activation represents a more sustained response such as that typified by infection with parasites. While the induction of MHC class II and co-stimulatory molecules (PD-L2) indicate these macrophages are activated, they express a distinct repertoire of cell surface receptors (mannose receptor, Mrc1; dectin-1, Clec7a; and Mgl1, Clec10A), and secreted products (Ym-1, Chi3l3; and FIZZ1, Retnla). c) Differential metabolism of l-arginine in classically and alternatively activated macrophages by inducible nitric oxide synthase (Nos2) and arginase 1, respectively. Odc1: ornithine decarboxylase; Oat: ornithine aminotransferase.

Figure 2. Intracellular mechanisms of inflammatory insulin resistance

Insulin action is transduced from the cell surface to cytoplasmic and nuclear responses via tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and -2. However, serine phosphorylation of these same substrates by JNK1 and IKKβ, the central mediators of stress and inflammatory responses, potently inhibits insulin action, thereby directly linking these responses to insulin resistance. In addition, the transcriptional activation of inflammatory genes by JNK1 and IKKβ induces insulin resistance in an autocrine and paracrine manner in tissues. Moreover, in states of obesity, JNK1 and IKKβ signaling pathways are activated by increased influx of free fatty acids and glucose.

Figure 3. Factors controlling recruitment and classical activation of ATMs

Increased intake of diets rich in saturated fatty acids induces obesity, resulting in recruitment of CCR2+ monocytes that differentiate into classically activated macrophages. The inflammatory milieu that promotes classical activation (M1) of ATMs in obese animals includes recruitment of CD8 cells, reduction in numbers of regulatory T cells (Tregs), and increased production of Th1-type cytokines. In addition, adipocyte hypertrophy induces ER stress and hypoxia, factors that eventually lead to cellular necrosis. In obese animals, CD8 cells and CAMs form crown-like structures around necrotic adipocytes. The dramatic increase in CAMs in obese adipose tissue negates the anti-inflammatory and homeostatic functions of AAMs, resulting in increased inflammation. AAMs: alternatively activated macrophages; CAMs: classically activated macrophages.

Figure 4. Functional differences between lean and obese adipose tissue

Adipose tissue from lean individuals comprises small, insulin-sensitive adipocytes that secrete large amounts of insulin-sensitizing adipokines under the influence of alternatively (M2)-biased adipose tissue macrophages (ATMs). In contrast, adipose tissue from obese individuals displays an expanded and prominently classically (M1)-biased population of ATMs, which secrete a variety of potent inflammatory mediators, together with hypertrophic, insulin-resistant adipocytes.

Figure 5. Transcriptional mechanisms controlling alternative (M2) activation

The canonical pathway of alternative macrophage activation involves activation of STAT6 by the Th2 cytokines IL-4 and -13. STAT6 activation initiates a transcriptional program comprising both immunologic effector responses and metabolic adaptations necessary to sustain them. Among the metabolic targets of STAT6 are PPARγ and δ as well as related coactivator PGC-1β. The transcriptional synergy between these metabolic regulators and STAT6 serves to sustain the immune effector response as well as direct metabolic adaptation for oxidative metabolism.

Figure 6. Effects of alternatively activated (M2) macrophages on adipose tissue

Dietary intake of unsaturated fatty acids and maintenance of lean body mass results in alternative activation (M2) of ATMs via activation of PPARγ/δ, local production of Th2 cytokines IL-4, IL-13, and IL-10, and release of trophic adipokines, such as adiponectin. The alternative phenotype protects against IR through the direct suppression of inflammation as well as through positive homeostatic maintenance activities, including remodeling of adipose tissue to prevent hypoxia and prompt clearance of apoptotic cells to prevent cellular necrosis. AAMs: alternatively activated macrophages; CAMs: classically activated macrophages.