**4. Inflammation and macrophages**

cell energy stores [35], induce DNA strand breaks [36], enhance cell adhesion [37], increase

In the research presented in **Figure 2**, the concentration of ROS seems to be considered the concentration of a crucial signalling molecule. Low concentrations of generated ROS are believed to be critical for metabolic adaptation in the organelle. Moderate concentrations of ROS can be produced and released by stress; pathogen-infected and bacterial endotoxin lipopolysaccharide (LPS) are involved in the inflammatory response. The high concentration of ROS in the induced apoptosis/autophagy process can cause cell death [39] and initiate self-

**Figure 2.** Concentration of generated ROS may involve in the different physiological response. At the low concentration, the ROS regulate in the redox signalling, and at the moderate concentration of induced ROS which participated in the inflammation process. At the high level of ROS concentration increased and was to be involved in the cellular

Macrophages, which are present in almost all body tissue and display distinct location-specific phenotypes and gene expression profiles, display remarkable functional diversity in innate immune responses, tissue development and tissue homeostasis [41]. In different organs, the resident macrophages are given various appellations: microglia cells have fundamental importance in assessing the pathogenetic significance of perivascular inflammatory phenomena within the brain [42]; Kupffer cells are resident and recruited macrophages that play major roles in the homeostatic function of the liver and in its response to tissue damage [43]; alveolar macrophages are key determinants pulmonary immune responses and in the lung inflammation caused by asthma [44]. Previously, it was hypothesised that tissue macrophages were recruited from circulating blood monocytes. Recent studies have demonstrated that tissue macrophages such as microglia, Kupffer cells and Langerhans cells are established prenatally

endothelial tissue permeability [38] and stimulate the release of cytokines.

healing [40].

170 Wound Healing - New insights into Ancient Challenges

apoptosis.

**3. Tissue resident macrophages**

Inflammation is an important adaptive physiological response of the organism. Inflammation response embodies a complicated interaction among molecular mediators and cells. It globally affects the leukocytes, also the lymphocytes in their micro-environmental function and organisation [48]. Throughout their response, numerous factors are involved in the classical immune response. Macrophages detain a critical role in the uptake and degradation of infectious agents and senescent cells; they also play crucial roles in tissue growth, tissue remodelling and inflammation by producing oxidants, proteinases and anti-microbial peptide [40].

Resident macrophages sense exogenous or endogenous danger signals (e.g., bacterial products or necrotic cell debris) through PRRs. In response to Toll-like receptor (TLR) ligands and interferon-gamma (IFN-γ) or IL-4/IL-13, macrophages undergo M1 (classical) or M2 (alternative) activation. The activation of M1 and M2 macrophages mirrors TH1-TH2 polarisation; M1 and M2 activation span the extremes of a continuum. M1 macrophages, which display a morphology that depends on their tissue location, develop in response to stimulation with IFN-γ and microbial products such as LPS. M1 macrophages can secrete substantial amounts of pro-inflammatory cytokines, such as IL-1β, IL-15, IL-18, TNF-α and IL-12 [53]. M2 macrophages adapt to similarities and differences between IL-4, TLR ligands with IL-10 and glucocorticoids [54].

The phenotypes of M1 and M2 macrophages exhibit observable differences. The M1 phenotype is characterised by the expression of high levels of pro-inflammatory cytokines, high production of reactive nitrogen and oxygen intermediates, promotion of Th1 response and antimicrobial and tumour-inhibiting activity [43]. The M2 macrophage uses immune inhibitory effects to secrete large amounts of IL-10, TGF-β, and C-C motif chemokine ligands 17 (CCL17) and CCL22. Moreover, the M2 macrophage attracts non-cytotoxic Treg and Type 2 T-helper cells (TH2 cells) to aggregate in tumour tissue, inhibit T-cell differentiation and function, lower cytotoxic T-cell function, induce T-cell apoptosis, secrete CCL18 and attract naive T cells [55].


**Table 1.** Regulators in the M1 and M2 macrophage.

Macrophage polarisation is highly related to expressions of various TLRs on macrophages [56, 57]. The evidence indicates that TLR signalling (e.g., TLR4), which is activated by LPS and other microbial ligands, drives macrophages to prefer the M1 phenotype. In this reaction, MyD88 and TRIF activate a cascade of kinases, including IRAK4, TRAF6 and IKKβ; this results in the activation of nuclear factor kappa B (NF-κB), which drives the macrophage forward to the M1 phenotype. By contrast, IL-4 and IL-13 drive the macrophage's phenotype forward to M2. Activation of STAT6 through the IL-4 receptor alpha (IL-4Rα) and IL-10 induce activation of STAT3 through receptor IL-10R, which activates JAK1 and JAK3 (38), causing STAT6 activation [58, 59]. IL-10, TGF-β, IL-4 and IL-13 enhance inflammation and cellular immune response with NO, which is generated through IFN-γ-induced iNOS and is reduced in macrophages by Arg1 interactions with mast cells, basophils, eosinophils, NKT cells, IgE and selected subclasses of IgG. This promotes allergies and hypersensitivity [60] (**Table 1**).
