Macrophage polarization in inflammatory diseases.

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Abstract

Diversity and plasticity are two hallmarks of macrophages. M1 macrophages (classically activated macrophages) are pro-inflammatory and have a central role in host defense against infection, while M2 macrophages (alternatively activated macrophages) are associated with responses to anti-inflammatory reactions and tissue remodeling, and they represent two terminals of the full spectrum of macrophage activation. Transformation of different phenotypes of macrophages regulates the initiation, development, and cessation of inflammatory diseases. Here we reviewed the characters and functions of macrophage polarization in infection, atherosclerosis, obesity, tumor, asthma, and sepsis, and proposed that targeting macrophage polarization and skewing their phenotype to adapt to the microenvironment might hold great promise for the treatment of inflammatory diseases.

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Most cited references 55

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Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance.

Justin Odegaard, Roberto Ricardo-Gonzalez, Matthew H Goforth … (2007)

Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.

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Alveolar macrophages: plasticity in a tissue-specific context.

Tracy Hussell, Thomas Bell (2014)

Alveolar macrophages exist in a unique microenvironment and, despite historical evidence showing that they are in close contact with the respiratory epithelium, have until recently been investigated in isolation. The microenvironment of the airway lumen has a considerable influence on many aspects of alveolar macrophage phenotype, function and turnover. As the lungs adapt to environmental challenges, so too do alveolar macrophages adapt to accommodate the ever-changing needs of the tissue. In this Review, we discuss the unique characteristics of alveolar macrophages, the mechanisms that drive their adaptation and the direct and indirect influences of epithelial cells on them. We also highlight how airway luminal macrophages function as sentinels of a healthy state and how they do not respond in a pro-inflammatory manner to antigens that do not disrupt lung structure. The unique tissue location and function of alveolar macrophages distinguish them from other macrophage populations and suggest that it is important to classify macrophages according to the site that they occupy.

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IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses.

Thomas Krausgruber, Katrina Blazek, Tim Smallie … (2011)

Polymorphisms in the gene encoding the transcription factor IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Here we show that IRF5 expression in macrophages was reversibly induced by inflammatory stimuli and contributed to the plasticity of macrophage polarization. High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. Consequently, those macrophages set up the environment for a potent T helper type 1 (T(H)1)-T(H)17 response. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively. Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor.

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Author and article information

Journal

Journal ID (iso-abbrev): Int. J. Biol. Sci.

Title: International journal of biological sciences

Publisher: Ivyspring International Publisher

ISSN (Electronic): 1449-2288

ISSN (Print): 1449-2288

Publication date (Electronic): 2014

Volume: 10

Issue: 5

Affiliations

[1 ] 1. Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R.China;

[2 ] 2. Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing 100048, P.R.China;

[3 ] 2. Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing 100048, P.R.China; ; 3. State Key Laboratory of Kidney Disease, the Chinese PLA General Hospital, Beijing 100853, P.R.China.

Article

Publisher Item ID: ijbsv10p0520

DOI: 10.7150/ijbs.8879

PMC ID: 4046879

PubMed ID: 24910531

SO-VID: 46a82436-04eb-4661-9982-6aba5856db1b

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Keywords: alternatively activated macrophage,immune regulation.,inflammatory diseases,signal pathways,macrophage polarization

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Keywords: alternatively activated macrophage, immune regulation., inflammatory diseases, signal pathways, macrophage polarization

Macrophage polarization in inflammatory diseases.

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Abstract

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Most cited references 55

Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance.

Alveolar macrophages: plasticity in a tissue-specific context.

IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses.

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