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Macrophage-mediated inflammation in metabolic disease

Nature Reviews Immunology volume 11, pages 738–749 (2011)Cite this article

Subjects

Key Points

  • Inflammation is a pathogenic link between obesity and insulin resistance.

  • Adipose tissue macrophages display characteristics ranging from alternative to classical, and these reflect the nutritional state of the organism.

  • Obesity leads to the recruitment of CCR2+LY6C+ monocytes, which give rise to pro-inflammatory, classically activated macrophages in white adipose tissue.

  • Saturated fatty acids, potentially acting via Toll-like receptor 4, drive classical macrophage activation in the obese state.

  • Alternatively activated macrophages populate lean adipose tissue and are associated with insulin sensitivity.

  • Eosinophil-derived interleukin-4 supports alternative activation of adipose tissue macrophages to promote insulin sensitivity.

  • Peroxisome proliferator-activated receptor-γ (PPARγ) and PPARδ, acting as fatty acid sensors in macrophages, cooperate with signal transducer and activator of transcription 6 and Krüppel-like factor 4 to sustain alternative macrophage activation.

  • Chronic overnutrition results in the activation of adaptive immune responses, which synergize with macrophage-mediated inflammation to promote insulin resistance.

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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Figure 1: Classically activated macrophages contribute to adipose tissue inflammation and insulin resistance.
Figure 2: Crosstalk between innate and adaptive immune cells in adipose tissue.
Figure 3: Alternatively activated macrophages protect against obesity and insulin resistance.
Figure 4: Infection-induced insulin resistance is adaptive.
Figure 5: TH-type immunity enhances insulin action.

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Acknowledgements

We thank members of the Chawla laboratory and A. Loh for valuable comments on the manuscript, and K. Vicari and R. Levinson for assistance with illustrations. The authors' work was supported by grants from the US National Institutes of Health (NIH; DK076760 and HL076746), a Larry L. Hillblom Foundation Network Grant and an NIH Director's Pioneer Award (DP1OD006415) to A.C. Support was also provided by a Stanford Graduate Fellowship to K.D.N. and an A-STAR Fellowship to Y.P.G. Owing to space limitations, we regret that we are unable to cite all relevant publications on this topic from our colleagues.

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Authors and Affiliations

  1. Cardiovascular Research Institute, University of California San Francisco, 94158-9001, California, USA

    Ajay Chawla & Y. P. Sharon Goh

  2. Departments of Physiology and Medicine, University of California San Francisco, 94158-9001, California, USA

    Ajay Chawla & Khoa D. Nguyen

  3. Immunology Program, Stanford University, Stanford, 94305, California, USA

    Khoa D. Nguyen & Y. P. Sharon Goh

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  1. Ajay Chawla
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Correspondence to Ajay Chawla.

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Glossary

Insulin resistance

A physiological or pathophysiological state in which insulin becomes less effective at lowering serum glucose owing to decreased responsiveness of insulin target tissues, such as adipose tissue, skeletal muscle and liver.

Adipokines

Hormones and/or cytokines secreted by adipose tissue, such as leptin and adiponectin.

Alternatively activated (M2) phenotype

A macrophage phenotype that is stimulated by the TH2-type cytokines interleukin-4 (IL-4) and IL-13. These macrophages express arginase 1, the mannose receptor (CD206) and CD301. Chronic states of helminth infections are associated with alternatively activated macrophages.

Classical (M1) phenotype

A pro-inflammatory, antimicrobial programme of macrophage activation induced by interferon-γ and Toll-like receptor ligands.

CD11c-DTR mice

Transgenic mice that express the diphtheria toxin receptor (DTR) under the control of the Cd11c promoter. Injection of diphtheria toxin allows for specific ablation of CD11c+ cells from these mice.

CD4+ T cells

A T cell subset that expresses the glycoprotein CD4, which assists the T cell receptor in the recognition of antigens presented on MHC class II molecules by antigen-presenting cells.

TH1 cells

(T helper 1 cells). TH1 cells secrete interferon-γ and tumour necrosis factor to promote cell-mediated immunity by supporting the classical activation of macrophages and the proliferation of cytotoxic CD8+ T cells.

CD8+ T cells

CD8+ T cells express the co-receptor CD8, which together with the T cell receptor recognizes antigens bound to MHC class I molecules. Activated CD8+ T cells induce the death of virus-infected or damaged cells.

TH2 cells

(T helper 2 cells). TH2 cells secrete the cytokines interleukin-4 (IL-4), IL-5 and IL-13 to stimulate humoral immunity (B cells) and alternative macrophage activation.

B2 cells

Conventional bone marrow-derived B cells that make up the bulk of splenic B cells. They express high levels of B220 and membrane-bound IgD.

Mineralocorticoid

A steroid hormone that regulates the concentration of minerals, such as sodium and potassium, in extracellular fluids. These hormones bind and activate the mineralcorticoid receptor to mediate their transcriptional effects.

4get reporter mice

Knock-in mice that express enhanced green fluorescent protein from the interleukin-4 (Il4) locus, allowing for the detection of cells competent for IL-4 production.

Pentose phosphate pathway

This pathway uses glucose to generate NADPH and pentose sugars (such as ribose). The first (oxidative) phase converts glucose-6-phosphate to ribulose-5-phosphate and generates NADPH. The second (non-oxidative) phase synthesizes other sugars from ribulose-5-phosphate.

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Chawla, A., Nguyen, K. & Goh, Y. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 11, 738–749 (2011). https://doi.org/10.1038/nri3071

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