Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines

Murray, Peter J.; Allen, Judith E.; Biswas, Subhra K.; Fisher, Edward A.; Gilroy, Derek W.; Goerdt, Sergij; Gordon, Siamon; Hamilton, John A.; Ivashkiv, Lionel B.; Lawrence, Toby; Locati, Massimo; Mantovani, Alberto; Martínez, Fernando O.; Mège, Jean Louis; Mosser, David M.; Natoli, Gioacchino; Saeij, Jeroen P. J.; Schultze, Joachim L.; Shirey, Kari Ann; Sica, Antonio; Suttles, Jill; Udalova, Irina A.; Ginderachter, Jo A. Van; Vogel, Stefanie N.; Wynn, Thomas A.

doi:10.1016/j.immuni.2014.07.009

Cited by 507 publications

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“…Newly recommended guidelines for the nomenclature of the macrophage activation process are based on three principles: source of macrophages, definition of activators and a consensus collection of markers to describe macrophage activation [23]. On the basis of these guidelines, the human CD16 + CD163 + MerTK + pSTAT3 + activation program described in this study within the TB context is reasonably related to the proposed "M(IL-10)" nomenclature.…”

Section: Discussionmentioning

confidence: 99%

“…Monocytes conditioned with cmMTB differentiated into cells displaying an equivalent or low- er expression of M1 polarization markers (i.e., CD86, HLA-DR, FCAR and Serpine1) compared with cells differentiated in the presence of cmCTR (Supplementary information, Figure S1A-S1B). By contrast, the expression of markers related to M2 macrophage activation, such as CD16, CD163, MerTK, CD206, AMAC1 and CD200R1 [23][24][25][26][27], was upregulated in cmMTB-conditioned cells ( Figure 1B, Supplementary information, Figure S1B). Similarly, the expression of CCR2 and CCR5 chemokine receptors was higher in the presence of cmMTB, supporting the acquisition of the M2 program (Supplementary information, Figure S1C) [28,29].…”

Section: Differentiation Of Human Monocytes Towards An M2-like Activamentioning

confidence: 99%

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Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

et al. 2015

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The human CD14 + monocyte compartment is composed by two subsets based on CD16 expression. We previously reported that this compartment is perturbed in tuberculosis (TB) patients, as reflected by the expansion of CD16 + monocytes along with disease severity. Whether this unbalance is beneficial or detrimental to host defense remains to be elucidated. Here in the context of active TB, we demonstrate that human monocytes are predisposed to differentiate towards an anti-inflammatory (M2-like) macrophage activation program characterized by the CD16 + CD163 + MerTK + pSTAT3 + phenotype and functional properties such as enhanced protease-dependent motility, pathogen permissivity and immunomodulation. This process is dependent on STAT3 activation, and loss-of-function experiments point towards a detrimental role in host defense against TB. Importantly, we provide a critical correlation between the abundance of the CD16 + CD163 + MerTK + pSTAT3 + cells and the progression of the disease either at the local level in a non-human primate tuberculous granuloma context, or at the systemic level through the detection of the soluble form of CD163 in human sera. Collectively, this study argues for the pathogenic role of the CD16 + C-D163 + MerTK + pSTAT3 + monocyte-to-macrophage differentiation program and its potential as a target for TB therapy, and promotes the detection of circulating CD163 as a potential biomarker for disease progression and monitoring of treatment efficacy.

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Section: Discussionmentioning

confidence: 99%

Section: Differentiation Of Human Monocytes Towards An M2-like Activamentioning

confidence: 99%

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

et al. 2015

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“…Similarly to macrophages, neutrophil polarization probably exists as a spectrum of activation states, rather than only two extremes. We suggest that researchers should follow the recent advances in the macrophage field and apply a combinatorial nomenclature that describes neutrophil activation status 99 .…”

Section: Tumor-induced Neutrophil Polarization and Activationmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

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SummaryNeutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view.The traditionally held belief that neutrophils are inert bystanders is being challenged by recent literature. Emerging evidence indicates that tumors manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumor behavior. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets. 2The name neutrophil -given to polymorphonuclear, granulocytic cells by Paul Ehrlich in the late 19th century -is based on the inability of these cells to retain acidic or basic dyes and for their preferential uptake of pH neutral dyes 1 . Although their neutral staining led to the identification of these cells, neutrophils in the cancer setting are anything but neutral.Neutrophils in tumor-bearing hosts can oppose or potentiate cancer progression. These two types of behavior are controlled by signals emanating from cancer cells or stromal cells within the tumor microenvironment, which educate neutrophils to execute the demise of the tumor or facilitate support networks that lead to its expansive spread. These functions can occur locally in or around the tumor microenvironment, as well as systemically in distant organs.Until the past few years, other immune cells such as macrophages have overshadowed the role of neutrophils in cancer. But recent studies and the development of new genetic tools have provided the cancer community with new insights into the profound influence of these dynamic cells by uncovering distinct capabilities for neutrophils throughout each step of carcinogenesis: from tumor initiation to primary tumor growth to metastasis.During these processes, neutrophils take on different phenotypes and sometimes opposing functions. Emerging evidence also indicates that these cells are highly influential, and are able to change the behavior of other tumor-associated cell types -primarily other immune cells. In this Review, we focus on how tumors manipulate the generation and release of neutrophils from the bone marrow. We discuss the mechanisms identified in animal models by which neutrophils participate in tumor initiation, growth and metastasis. Finally, we highlight the potential of these cells as clinical biomarkers and therapeutic targets. In humans, neutrophils are the most abundant immune cell population, representing 50-70% of all leukocytes. Over 10 11 neutrophils may be produced per day 2 , and tumors can increase this number by even more. Indeed, patients with various cancer types, including but not limited to breast, lung and colorectal cancer, often exhibit increased numbers of circulating neutrophils 3,4 . Recent studies have identified key pathways that tumors exploit to disrupt normal neutrophil homeostasis and these are discuss...

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“…Adherent monocytes were cultured in the presence of 4 ng/mL colony-stimulating factor 1 (CSF-1) to generate monocyte-derived macrophages, hereby referred to as M(CSF-1) in accordance with the recently published macrophage nomenclature guidelines. 22 They were cultured for 4 days in Iscove's Dulbecco's modified Eagle's medium (Life Technologies, Paisley, UK) containing 10% autologous serum and prepared by recalcification of platelet-rich plasma (12-well plates, 37 C in 5% CO 2 ). M(CSF-1) were exposed to DMSO…”

Section: Human Peripheral Blood Monocyte Isolation and Macrophage Difmentioning

confidence: 99%

“…A tenth of mouse peritoneal macrophages (10.14 AE 6.41) and a quarter of lesion resident macrophages (24.82 AE 5.57) were immunopositive for ERa ( Figure 1, J and K), with all GFP þ cells being immunopositive for ERb ( Figure 1L). Human peripheral blood monocytes were isolated and differentiated into macrophages that are classified as being at the alternative end of the macrophage activation spectrum 22 Migration score was based on percentage cells mobilized and distance migrated. Macrophages; n Z 4 patients, embryonic rat DRGs; n Z 4 pregnant dams.…”

Section: Erb Is the Predominant Er Expressed By Lesion-resident Macromentioning

confidence: 99%

Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis

Greaves

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Esnal-Zufiurre

et al. 2015

The American Journal of Pathology

135

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Endometriosis occurs in approximately 10% of women and is associated with persistent pelvic pain. It is defined by the presence of endometrial tissue (lesions) outside the uterus, most commonly on the peritoneum. Peripheral neuroinflammation, a process characterized by the infiltration of nerve fibers and macrophages into lesions, plays a pivotal role in endometriosis-associated pain. Our objective was to determine the role of estradiol (E2) in regulating the interaction between macrophages and nerves in peritoneal endometriosis. By using human tissues and a mouse model of endometriosis, we demonstrate that macrophages in lesions recovered from women and mice are immunopositive for estrogen receptor b, with up to 20% being estrogen receptor a positive. In mice, treatment with E2 increased the number of macrophages in lesions as well as concentrations of mRNAs encoded by Csf1, Nt3, and the tyrosine kinase neurotrophin receptor, TrkB. By using in vitro models, we determined that the treatment of rat dorsal root ganglia neurons with E2 increased mRNA concentrations of the chemokine C-C motif ligand 2 that stimulated migration of colony-stimulating factor 1edifferentiated macrophages. Conversely, incubation of colony-stimulating factor 1 macrophages with E2 increased concentrations of brainderived neurotrophic factor and neurotrophin 3, which stimulated neurite outgrowth from ganglia explants. In summary, we demonstrate a key role for E2 in stimulating macrophage-nerve interactions, providing novel evidence that endometriosis is an estrogen-dependent neuroinflammatory disorder. Endometriosis affects 10% of reproductive age women and is associated with persistent pelvic pain. 1 It is defined by the presence of endometrial-like tissue (lesions) found outside the uterus, most commonly on the peritoneum. The mechanisms underlying endometriosis-associated pain are poorly understood, but it has been postulated that estrogen-dependent neuroinflammation may be involved. 2 Notably, the presence of endometrial tissue fragments on the peritoneum elicits an immune response, including recruitment of macrophages, 3 blood vessels, and nerve fibers into the resultant lesions. 4,5 Within the lesions, CD68 þ macrophages have been detected in close association with nerve fibers. 6 Studies investigating macrophage activation and recruitment have revealed that endometriosis-associated macrophages exhibit a phenotype consistent with the alternative end of the macrophage activation spectrum. 7,8 In a mouse model of endometriosis that included cell transfer of polarized macrophages, Bacci et al 7 reported that mice injected with proinflammatory macrophages [macrophage (interferon g)] developed microscopic lesions, but those injected with alternatively activated macrophages [macrophage (IL-4)] developed larger lesions with a well-developed vasculature. Our studies in a mouse model of endometriosis have revealed that macrophages resident in peritoneal lesions can originate from both the peritoneum and the endometrium. 9

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Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines

Cited by 507 publications

References 0 publications

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

Neutrophils in cancer: neutral no more

Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis

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