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. 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. In addition to chemical stimulation, it has been shown that the stiffness of the underlying substrate a macrophage is grown on can direct polarization state, functional roles and migration mode. A continuum of M1-M2 polarization may arise even in the absence of polarizing cytokines and differences in substrate stiffness. M1 macrophages were described as the pro-inflammatory type, important in direct host-defense against pathogens, such as phagocytosis and secretion of pro-inflammatory cytokines and microbicidal molecules. M2 macrophages were described to have quite the opposite function: regulation of the resolution phase of inflammation and the repair of damaged tissues. Later, more extensive in vitro and ex vivo studies have shown that macrophage phenotypes are much more diverse, overlapping with each other in terms of gene expression and function, revealing that these many hybrid states form a continuum of activation states which depend on the microenvironment. Moreover, in vivo, there is a high diversity in gene expression profile between different populations of tissue macrophages. Macrophage activation spectrum is thus considered to be wider, involving complex regulatory pathway to response to plethora of different signals from the environment. The diversity of macrophage phenotypes still remain to be fully characterized in vivo. The imbalance of the macrophage types is related to a number of immunity-related diseases. For example, it has been shown that increased M1/M2 ratio correlates with development of inflammatory bowel disease, as well as obesity in mice. On the other side, in vitro experiments implicated M2 macrophages as the primary mediators of tissue fibrosis. Several studies have associated the fibrotic profile of M2 macrophages with the pathogenesis of systemic sclerosis.
Types
M1 Classically activated macrophages (M1) were named by George Mackaness in the 1960s. M1-activation in vitro is evoked by treatment with TLR ligands such as bacterial lipopolysaccharide (LPS) - typical for Gram-negative bacteria and lipoteichoic acid (LTA) - typical for Gram-positive bacteria, granulocyte-macrophage colony-stimulating factor (GM-CSF) or combination of LPS and interferon-gamma (IFN-γ). Similarly in vivo, classically activated macrophages arise in response to IFN-γ produced by Th1 lymphocytes or by natural killer cells (NK), and tumor-necrosis factor (TNF), produced by antigen-presenting cells (APCs). M1-activated macrophages express transcription factors such as interferon regulatory factor (IRF5), nuclear factor of kappa light polypeptide gene enhancer (NF-κB), activator protein (AP-1) and STAT1. This leads to enhanced microbicidal capacity and secretion of high levels of pro-inflammatory cytokines: e.g. IFN-γ, IL-1, IL-6, IL-12, IL-23 and TNFα. Moreover, to increase their pathogen-killing ability, they produce increased amounts of chemicals called reactive oxygen species (ROS) and nitrogen radicals (caused by upregulation of inducible NO synthase iNOS). Thanks to their ability to fight pathogens, M1 macrophages are present during acute infectious diseases. A number of studies have shown that bacterial infection induces polarization of macrophages toward the M1 phenotype, resulting in phagocytosis and intracellular killing of bacteria in vitro and in vivo. For instance, Listeria monocytogenes, a Gram-positive bacteria causing listeriosis is shown to induce an M1 polarization, as well as Salmonella Typhi (the agent of typhoid fever) and Salmonella Typhimurium (causing gastroenteritis), which are shown to induce the M1 polarization of human and murine macrophages. Macrophages are polarized toward the M1 profile during the early phase of Mycobacterium tuberculosis infection, as well as other mycobacterial species such as Mycobacterium ulcerans (causing Buruli ulcer disease) and Mycobacterium avium. 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. In order to counteract the inflammatory response, macrophages undergo apoptosis or polarize to an M2 phenotype to protect the host from the excessive injury.
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