Macrophage polarization
Macrophage polarization is a process by which macrophages adopt different functional programs in response to the signals from their microenvironment. This ability is connected to their multiple roles in the organism: they are powerful effector cells of the innate immune system, but also important in removal of cellular debris, embryonic development and tissue repair.[1]
By simplified classification, macrophage phenotype has been divided into 2 groups: M1 (classically activated macrophages) and M2 (alternatively activated macrophages). This broad classification was based on in vitro studies, in which cultured macrophages were treated with molecules that stimulated their phenotype switching to a particular state.
The imbalance of the macrophage types is related to a number of immunity-related diseases.[12][13] For example, it has been shown that increased M1/M2 ratio correlates with development of inflammatory bowel disease,[14][15] as well as obesity in mice.[16][17][18] On the other side, in vitro experiments implicated M2 macrophages as the primary mediators of tissue fibrosis.[13] Several studies have associated the fibrotic profile of M2 macrophages with the pathogenesis of systemic sclerosis.[12][19]
Types
M1
Classically activated macrophages (M1) were named by
M1-activated macrophages express transcription factors such as interferon regulatory factor (
Improper and untimely control of M1 macrophage-mediated inflammatory response can lead to disruption of normal tissue homeostasis and impede vascular repair. An uncontrolled production of pro-inflammatory cytokines during the inflammation can lead to the formation of cytokine storm, thereby contributing to the pathogenesis of severe sepsis.[27] In order to counteract the inflammatory response, macrophages undergo apoptosis or polarize to an M2 phenotype to protect the host from the excessive injury.[23]
M2
Alternatively activated macrophages (M2) were discovered in early 1990s and named according to previously-discovered Th2 cell-mediated anti-inflammatory response.[23] M2 macrophages resolve inflammation, help tissue healing, tolerate self-antigens and certain neoantigens (for example apoptotic cells, symbiont cells, gametes and cells of the embryo in the uterus). M2 macrophages hence govern functions at the interfaces of immunity, tissue development and turnover, metabolism, and endocrine signaling.[28] It is shown in vitro that macrophage treatment with IL-4 and IL-13 leads to inhibition of pro-inflammatory signals production and upregulation of scavenging mannose receptor CD206.[23] Further studies have shown that M2 polarization may be induced through different activation signals leading in fact to different M2 phenotypes having different roles. It has first been suggested that M2 macrophages can be divided in two groups: regulatory and wound-healing macrophages. Regulatory macrophages were described to have anti-inflammatory properties, which are important in resolutive phases of the inflammation, producing the immunosuppressive cytokine IL-10. Differentiation toward the regulatory macrophage phenotype may be triggered by immune complexes, prostaglandins, apoptotic cells and IL-10. On the other side, wound healing macrophages were shown to produce IL-4 and upregulate arginase activity, which is the enzyme enrolled in production of polyamines and collagen, thus regenerating the damaged tissue.[5][6]
Further investigation of M2 subtypes led to even more complex systematization, where the authors describe M2a, M2b, and M2c subtype.
Although M2 activation state involves heterogeneous macrophage populations, some markers are shared between subtypes, thus the strict macrophage division into subtypes is not possible so far. In mice, CD206 or the mannose receptor marker can be used to differentiate the M2 from M1. Moreover, the in vivo translation of these M2 subdivisions is difficult. Tissues contain complex range of stimuli leading to mixed macrophage populations with a wide spectrum of activation states.[7][30]
Continuum of polarization states
A lot remains to be learned about macrophage polarized activation states and their role in immune response. Since there is not a rigid barrier between described macrophage phenotypes and that known markers are expressed by more than one of these activation states,[5][30] it is impossible so far to classify macrophage subtypes in proper and precise way. Thus their differences are rather considered as a continuum of functional states without clear boundaries. Moreover, it is observed that macrophage states are changing during the time course of the inflammation and disease.[30][31] This plasticity of macrophage phenotype has added to the confusion regarding the existence of individual macrophage sub-types in vivo.[30][32]
Tumour associated macrophages
Tissue resident macrophages
Some macrophages are known to be residing in the tissues and help in maintaining the tissue microenvironment. These came to be known as tissue resident macrophages(TRMs). The TRMs in the pancreatic islets are known to be inflammatory in nature and fall under the M1 category.[40]
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