**1.1 Development of macrophages**

Macrophages are originated from variety of cells. In the early development, it depends on the tissues; however, macrophages are derived from yolk sac and replaced by the macrophages derived from liver and bone marrow [1]. Tissue resident macrophages are divided into two types, macrophages derived from circulating monocytes and having other origins including yolk sac, embryonic liver, and embryo near dorsal aorta-derived macrophages. In the adulthood, they are independently kept from their original monocytes. Tissue-specific macrophages differentiate from circulating monocytes by the ability of migration at the time of inflammation. Dendritic cells differentiate from monocytes as well as macrophages. Macrophages have variety of

morphologies and phenotypes because they distribute in many organs and tissues. Instead of neutrophils that live only few days, the life span of the macrophages is several months. The diameter of the human macrophage is about 21 μm.

#### **1.2 Differentiation and subtypes**

Macrophages differentiate from premature M0 to M1 or M2 phenotypes depending on various factors from the signal transduction molecules, growth factors, transcription factors, and epigenetic or post-transduction changes to cytokines, cell adherence molecules, and metabolites [2]. Furthermore, macrophages change their activation state in response to microbes and microbial products like LPS. Recently, it is said that the classifications of macrophages are not easy because of the plasticity of the macrophages.

M1 macrophages are the so-called classically activated macrophages, pro-inflammatory macrophages, and killer macrophages. M1 macrophages produce high levels of IL-12 after the stimulation of LPS and IFN-γ. The feature of M1 macrophages is possessing specific pathways which converts arginine into "killer molecules" nitric oxide. M1 macrophage is the phenotype observed in early inflammation phase activated by IFN-γ, TNF, and damage-associated molecular patterns (DAMPS). They show high antigen presenting ability, producing high amounts of NO and reactive oxygen spices (ROS), showing increased expression of IL-12 and IL-23, and decreased IL-10 expression. In addition, M1 macrophages express high levels of MHC class II molecules, CD68, CD80, and Th1 cell-inducing chemokine CXCL9 and CXCL12 [3].

M2 macrophages are called alternatively activated macrophages and wound healing macrophages divided into M2a, M2b, M2c, and M2d phenotypes. They are a typical phenotype of tissue-resident macrophages and participate in constructive process including wound healing and tissue repair. These macrophages are stimulated by several factors including parasitic and fungal infection, immune complexes, apoptotic cells, macrophage colony stimulation factors (M-CSF), IL-13, TGF-β, and Th2 cytokine IL-4, and cytokines produced by Th2 cells like IL-25 and IL-33. Signal transduction pathways including STAT6, IRF4, PPARδ, and PPARδ are required for the differentiation of M2 macrophages. Generally, M2 macrophages produce low IL-1, IL-6, and TNF-α, whereas producing low IL-12. A typical feature of M2 macrophages is converting arginine to ornithine "repair molecules." Ornithine is important for wound healing and required for vascular and endothelial regeneration. M2 macrophages are also important for clearance of pathogens, anti-inflammation, metabolism, wound healing, tissue regeneration, immune regulation, and progression of tumours. On the other hand, M2 macrophages induce tissue fibrosis in the lung and liver, and progressively stimulate tumour growth as tumour-related macrophages. M2 phenotypes are characterised by the expression of CD206, CD163, FIZZ1, and Ym1/2. There are four types of M2 macrophages a, b, c, and d. These are different by their cell surface markers, secreting cytokines, and biological function. However, the common feature of these M2 macrophages is the production of IL-10 [4].

M2a macrophages are activated by IL-4 or IL-13. IL-4 induces the expression of the mannose receptor (CD206). Upregulation of IL-10, TGF-β, CCL17, CCL18, and CCL22 induces cell proliferation, cell repair, and endocytosis of M2a macrophages.

Immune complex, toll-like receptor (TLR) and their ligands, and IL-1β activate M2b macrophages. When activated, these subtypes of macrophages produce both proinflammatory and anti-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-10. M2b macrophages work on immune response and regulation of inflammation. High IL-10-producing and low IL-12-producing M2b macrophages are the so-called *Macrophages: Phagocytosis, Antigen Presentation, and Activation of Immunity DOI: http://dx.doi.org/10.5772/intechopen.110832*

regulatory macrophages (Mreg). Mregs are recently focused on their ability to induce regulatory T cells (Treg) [5].

M2c macrophages are activated by glucocorticoid, IL-10, TGF-β, and inactivated macrophages. The feature of M2c macrophages is high expression of anti-inflammatory IL-10, TGF-β, CCL16, CCL18, and tyrosine-protein kinase MER (MerTK), which enhance phagocytosis activity.

TLR antagonist, IL-6, and adenosine activate M2d macrophages. Adenosine induces the expression of IL-10 and vascular endothelial growth factor (VEGF) and enhances angiogenesis and tumour progression.

M2 macrophages are important for the stability of blood vessels because they produce VEGF-A and TFG-β. In acute lesion, macrophages change their phenotype from M1 to M2; however, these changes will be lost in chronic lesion. This dysregulation results in insufficient M2 macrophages and induces the deficiency of growth factor. The lack of growth factors and anti-inflammatory cytokines from M2 macrophages and excess production of proinflammatory cytokines from M1 macrophage prevent sufficient repair of wound healing. Normally, depletion of neutrophils by apoptosis after eating debris and pathogens induces the switch of macrophages from M1 to M2, but inflammation is unnecessary at that time. Then, M1 macrophages cannot eat apoptosis-inducing neutrophils, and this phenomenon increases the numbers of macrophages and inflammation because of the dysregulation [6].
