Macrophage polarization

Macrophages can be activated in a variety of different ways, and the TH1 and TH2 cell subtypes have a profound impact on directing and maintaining macrophage activation. TH1 cells bind to macrophages that carry intracellular pathogens such as Listeria and Leishmania

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in vesicular compartments. These macrophages interact with TH1 cells via CD80-CD28, CD40-CD40L and MHCII-T cell receptor interaction and release of IL12 [1]. Subsequent IFNγ release by TH1 cells activates macrophages in a pro-inflammatory way, a process that has been termed M1 polarization [31], thus rendering them capable of fighting intracellular pathogens.

In contrast, the TH2 response is elicited in response to allergens or parasites such as helminths and can also be mounted in response to a weak antigen that is not sufficiently immunogenic to trigger a TH1 response. TH2 cells can activate macrophages by secretion of IL4 and IL13.

Unlike activation by IFNγ, IL4 and IL13 trigger an alternative activation of macrophages, which has been termed M2a polarization. This macrophage subtype is associated with allergy and TH2 inflammation [32]. In addition to the M2a subtype, further distinct polarization states have been described to be inducible in vitro, referred to as M2b and M2c. The focus herein will lie on M2a-stimulated macrophages, which will henceforth be denominated M2, as the M2a/b/c nomenclature has been discouraged (see below).

In vivo, the M1 and the M2 states represent two extremes of a broad spectrum of phenotypes that a macrophage can adopt [33]. Macrophages both require and promote a certain microenvironment, and their transient phenotype is a product of this delicate interplay. The pro-inflammatory microenvironment that arises at the site of an ongoing infection is primarily established by macrophages and leads to immune cell recruitment from the blood into the tissue and to the subsequent formation of the pro-inflammatory M1 macrophage subtype. The M1 macrophage actively participates in killing invading pathogens and infected cells by phagocytosis and lysis. The highly aggressive properties of this subtype need to be tightly controlled in order to prevent an excessive and inappropriate response to the present threat that might become deleterious to the host. Upon clearance of the infection, the cytokine microenvironment gradually shifts from pro-inflammatory to immunomodulatory, leading to a change of macrophage behavior. Phagocytosis of apoptotic cells primes macrophages to release anti-inflammatory mediators such as IL10 and TGFβ [34, 35]. This newly arising immunoregulatory subtype has long been considered to be inactive, but it has increasingly become clear that even though many pro-inflammatory functions are switched off, these so-called M2c macrophages show a defined pattern of activity that helps restoring the physiological state of the inflamed site. Their contribution to angiogenesis, wound repair and extracellular matrix restoration is crucial for the re-establishment of homeostasis. The effector cell that is required for these processes is the myofibroblast whose activation is triggered and

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maintained by M2 macrophage-derived TGFβ and platelet-derived growth factor (PDGF).

Furthermore, M2 macrophages can directly contribute to tissue rebuilding by phagocytosis of cellular debris [36]. It has recently been emphasized that the term “alternatively activated”

should be used for TH2-associated macrophages only, while “immunoregulatory” and “wound healing” macrophages are also entities of their own, respectively [37]. This differentiation is reflected in the M2a/b/c nomenclature as it was proposed in 2004 [32]. However, it has since become clear that this discrete attempt of categorization still overly simplifies the versatile nature of macrophage biology, which should rather be represented as a continuum of states [38, 39].

Other than in the wake of an M1-dominated inflammation, M2 macrophages can also arise as the primary macrophage response of the immune system, e.g. during parasite infection. It has been shown that the TH2 response that is initiated as a response to a parasite is able to trigger local macrophage proliferation, induced by the TH2 hallmark cytokine IL4. Unlike M1 macrophages that are thought to accumulate at the site of infection by elevated monocyte recruitment, IL4-induced M2 macrophages have been shown to expand in situ [40]. This observation discourages the hypothesis of an existing specific M2 monocyte precursor in the blood, again stressing the assumption that the plasticity of macrophages lies in their inherent versatility, not in lineage commitment. It is still unclear, though, how monocyte differentiation and recruitment is altered in the course and aftermath of inflammation to re-establish the tissue´s pre-inflammatory cell count and activation status [41].

Due to its modulatory properties, the M2 subtype can be found at the root of various diseases that are characterized by a skewed or suppressed immune response, such as cancer and allergy. Cancerous tissue usually carries a high load of macrophages that are polarized toward the M2 phenotype by tumor-derived substances such as CCL2, M-CSF/CSF1, TGFβ and IL10 [42]. Even though these M2-like tumor-associated macrophages (TAMs) contribute to vascularization and immunologic tolerance of the tumor tissue, they have therapeutic potential. Efforts to re-polarize these TAMs toward the more aggressive M1 subtype via the NFκB axis led to shrinking of the tumor size in a mouse model of IKKβ activity [43]. Similar results were obtained in a study using human TAMs purified from ovarian cancer ascites.

Their M2-like phenotype could be reversed in vitro by IFNγ administration, and the resulting M1-like phenotype showed increased tumoricidal properties [44].

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