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Review
. 2011 Oct 10;11(11):738-49.
doi: 10.1038/nri3071.

Macrophage-mediated inflammation in metabolic disease

Ajay Chawla  1 , Khoa D Nguyen, Y P Sharon Goh
Affiliations
Review

Macrophage-mediated inflammation in metabolic disease

Ajay Chawla et al. Nat Rev Immunol. .

Abstract

Metabolism and immunity are two fundamental systems of metazoans. The presence of immune cells, such as macrophages, in metabolic tissues suggests dynamic, ongoing crosstalk between these two regulatory systems. Here, we discuss how changes in the recruitment and activation of macrophages contribute to metabolic homeostasis. In particular, we focus our discussion on the pathogenic and protective functions of classically and alternatively activated macrophages, respectively, in experimental models of obesity and metabolic disease.

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Figures

Figure 1
Figure 1. Classically activated (M1) macrophages contribute to adipose tissue inflammation and insulin resistance
Obesity results in de novo recruitment of macrophages into adipose tissue, which promote adipose tissue inflammation and insulin resistance. In part, dietary saturated fatty acids activate Toll-like receptor 2 (TLR2) and TLR4 in adipose tissue macrophages, resulting in activation of interferon regulatory factor 3 (IRF3), activator protein 1 (AP1) and nuclear factor-κB (NF-κB) inflammatory signaling cascades. These pathways induce the production of pro-inflammatory cytokines such as tumour necrosis factor (TNF). Production of IL-1β results from activation of the NLRP3 inflammasome, potentially by ceramides, the synthesis of which is increased in obesity. These pro-inflammatory cytokines inhibit insulin action in adipocytes by activation of IKKb and JNK signaling pathways. Once initiated, these inflammatory cascades are perpetuated by the crosstalk between the inflamed adipocytes, classically activated (M1) adipose tissue macrophages and T and B cells via elaboration of various chemokines and chemotactic factors. Some of the identified chemotactic factors include CC-chemokine ligand 2 (CCL2) and osteopontin (OPN), the expression of which is induced in adipocytes and macrophages during obesity. Importantly, CCL2 leads to recruitment of Ly6C+CCR2+ inflammatory monocytes, which differentiate into classically activated adipose tissue macrophages to enhance adipose tissue inflammation. In addition, adipose tissue macrophages release CD5-like antigen (CD5L), which promotes lipolysis in adipocytes after being taken up by adipocytes via CD36-mediated endocytosis. In a feed-forward loop, the released fatty acids induce the expression of chemokines, leading to recruitment of Ly6C+CCR2+ inflammatory monocytes and macrophages into adipose tissue. Reciprocally, saturated fatty acids, and inflammatory cytokines (TNF and IL-1β) from adipocytes sustain activation of inflammatory cascades in classically activated adipose tissue macrophages. Mineralocorticoid (MR) signaling also contributes to classical activation of adipose tissue macrophages by inhibiting the IL-4- and peroxisome proliferator activated receptor-γ (PPARγ)-driven program of alternative activation, whereas decreases in adipose tissue eosinophils and circulating levels of adipokines (adiponectin) impair alternative activation and release the break on the inflammatory activation of adipose tissue macrophages, respectively.
Figure 2
Figure 2. Alternatively activated (M2) macrophages protect against obesity and insulin resistance
In lean animals, adipose tissue macrophages display an alternatively activated phenotype with reduced inflammatory potential and increased production of the insulin sensitizing cytokine interleukin-10 (IL-10). Eosinophils secrete IL-4 to induce alternative macrophage activation. Activation of signal transducer and activator of transcription 6 (STAT6) by IL-4 induces the transcriptional cascade involving the fatty acid sensors peroxisome proliferator-activated receptor δ (PPARδ), PPARγ and Kruppel-like factor 4 (KLF4), which synergize with STAT6 to sustain the alternative activation of ATMs. Adiponectin released by adipocytes also synergizes with IL-4 signaling to enhance alternative macrophage activation and reduce macrophage-mediated inflammation. Concurrently, unsaturated free fatty acids, such as omega-3 fatty acids, signal via G-protein coupled receptor 120 (GPR120) to dampen nuclear factor-κB (NF-κB) activation in adipose tissue macrophages. Disruption of mineralocorticoid signaling introduces an alternative bias in macrophage activation, whereas agonists of mineralocorticoid receptor (MR) potentiate classical activation.
Figure 3
Figure 3
Crosstalk between innate and adaptive immune cells in adipose tissue. CD4+ FOXP3+ Treg cells and alternatively activated macrophages, enriched in the visceral adipose tissue of lean mice, secrete IL-10 to enhance insulin action and glucose disposal in adipocytes. With over nutrition, engorged adipocytes undergo necrotic cell death, resulting in recruitment of classically activated macrophages to clear debris. In this context, adipose tissue macrophages expressing the prototypical molecules (MHC class II, CD1d, co-stimulatory molecules) and markers (CD11c) of antigen-presenting cells are potentially capable of presenting to T and B cells to promote adaptive immune responses. This is postulated to promote clonal expansion of CD4+ Th1 cells and increase infiltration by CD8+ T cells. In a feed forward loop, IFNγ production by CD4+ Th1 cells, and secretion of inflammatory cytokines and chemotactic factors by CD8+ T cells results in increased recruitment and classical activation of macrophages. Concomitant with this, numbers of immunosuppressive Treg cells decrease in adipose tissue with obesity, further contributing to the adipose tissue inflammation and insulin resistance. B cells, which infiltrate obese adipose tissue, can present antigens on MHC class I and II molecules to naïve T cells. IgG2c antibodies produced by mature B cells further amplifies adipose tissue inflammation and insulin resistance.
Figure 4
Figure 4. Infection-induced insulin resistance is adaptive
Bacterial infection of the host activates innate immune cells, resulting in the release of pro-inflammatory cytokines that mediate insulin resistance in metabolic tissues. Insulin resistance in the liver increases gluconeogenesis, whereas in muscle it decreases glucose disposal and increases breakdown of stored glycogen. This has the net effect of increasing circulating levels of glucose, a nutrient that is preferentially used by innate and adaptive immune cells to fuel their activation. In parallel, insulin resistance in adipose tissue decreases lipogenesis and increases lipolysis. The free fatty acids (FFAs) released by adipocytes are used to support the metabolic demands of immune and non-immune cells.
Figure 5
Figure 5
Th2-type immunity enhances insulin action. Parasitic helminths induce the prototypical Th2-type immune responses characterized by tissue eosinophilia, alternative macrophage activation, and increased production of Th2-type cytokines (IL-4 and IL-13), as well as IL-10. Each aspect of this anti-helminth immunity enhances insulin action in liver, adipose tissue, and potentially, muscle, the three primary organs involved in metabolic homeostasis. Lean adipose tissue contains abundant numbers of eosinophils (which are the primary producers of IL-4 and IL-13) that sustain alternative activation of adipose tissue macrophages. In a paracrine manner, alternatively activated macrophages protect against insulin resistance by directly suppressing the clonal expansion of Th1 cells and dampening the inflammation mediated by classically activated macrophages. While local production of IL-4 and IL-10 enhances insulin-stimulated glucose disposal in fat, IL-4 stimulates the anabolic actions of insulin in liver. The net effect of Th2-type immunity is to enhance nutrient storage by potentiating the anabolic actions of insulin in tissues.
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