**5. Inflammation and disease**

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].

**Macrophage M1 M2**

**Nuclear factor** NF-κB [43]

**Suppressor** SOCS-1 **of cytokine signalling** SOCS-2 **(SOCS)** SOCS-3

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

**Interferon regulatory factor** IRF-3 [61, 62] IRF-4 [63]

**Phenotype** iNOS [69, 70] YM-1 [71]

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**).

IRF-5 [64] IRF-8 [65]

(controversial) [58]

STAT-1 [66] STAT-3 [43]

IL-6 [72] Arg-1 [73, 74] TNF-α [75] Fizz-1 [76]

STAT-5 [67] SATA-6 [68]

IL-10 [77]

**Transcription factor**

**of transcription**

**(STAT)**

**Signal transducer and activator**

172 Wound Healing - New insights into Ancient Challenges

**(IRF)**

Accumulating evidence indicates that chronic low-grade inflammation contributes to the systemic metabolic dysfunction that is associated with inflammation disorders [78]. Cytokines and pathogen-associated molecular patterns have been shown to co-stimulate cell surface receptors, including TLRs, to initiate intra-cellular signalling that activates NF-κB. NF-κB activation was thought to induce the target gene's expression to promote cellular proliferation and to activate the immune response. However, research has revealed that NF-κB activation can occur in most cell types; recent reports have demonstrated that high level activation of NFκB signalling pathways in the liver, adipose tissue and central nervous system (CNS) is involved in the development of inflammation-associated metabolic diseases [79]. The mutants of the brain-specific serpin, neuroserpin, also form ordered polymers that accumulate within the ER of neurons; these mutations cause an autosomal-dominant type of dementia known as familial encephalopathy with neuroserpin inclusion bodies, which is believed to be an inflammation disorder [80, 81].

Research has shown that, in specific tissue lesions, extra-cellular lipid droplets are forming a core region surrounded by smooth muscle cells and collagen-rich matrix. Lymphocytes as the T cells, monocyte, macrophages and mast cells are infiltrating in the lesion particularly in regions where the atheroma grows. These immune cells also generate important signals in the defence cascade by producing the inflammatory cytokines, largely involved in the atherosclerotic process [82]. A case report indicated that Alzheimer's disease (AD) inflammation appears to arise from within the CNS. Little or no involvement of lymphocytes or monocytes in AD was observed beyond their normal brain surveillance. This observation has placed AD outside the realm of conventional neuroimmunologic studies that largely focus on humoral aspects of such CNS inflammatory disorders as multiple sclerosis [83]. Judging from published reports, we believe that metabolic disorders and even neuronal diseases are highly related to abnormal inflammation.
