5.4 Macrophages in autoinflammation and autoimmunity

The uncontrolled activation of macrophages in response to DAMPs recognized by various PRRs and apoptotic cells (uncontrolled phagocytosis) may lead to chronic and uncontrolled inflammation that may induce autoinflammation and autoimmune diseases including severe autoimmune anemia, systemic lupus erythematosus (SLE), and chronic arthritis [173–176]. The increased infiltration of macrophages into the brain (i.e., in meninges surrounding the CNS, the perivascular space, and the choroid plexus) is also reported in experimental autoimmune encephalitis (EAE), an animal model for multiple sclerosis (MS) [177, 178]. The chronic up-regulation of CCR2, CCL2, CCL3, CCL4, and CCL22 stimulates the process of macrophage accumulation at the sites of the brain affected during EAE [179, 180]. Both M1 and M2 macrophages play a crucial role in the pathogenesis of EAE or MS [180, 181]. Macrophages also play a very important role in the pathogenesis of rheumatoid arthritis (RA) by secreting various pro-inflammatory cytokines, controlling the generation and function of regulatory T cells (Tregs) via binding and release of transforming growth factor-β (TGFβ), and their therapeutic targeting proves beneficial to the patients [182–185]. Sjogren's syndrome (SS), a chronic autoimmune disease of exocrine glands specifically salivary glands and lacrimal glands causing also systemic autoimmune lesions also shows the accumulation of monocytes and macrophages in the inflamed lesions [185–187]. In addition to these autoimmune diseases, both M1 and M2 macrophages also play a crucial role in the pathogenesis of type 1 diabetes mellitus by contributing to the destruction of β cells of the pancreas through controlling the generation of Th1 cells and acting as antigen presenting cells (APCs) to stimulate cytotoxic CD8+ T cells (T1DM) [188–190].

## 5.5 Macrophages in metabolic diseases

Obesity is an altered stage of metabolism originating due to the increased availability of nutrients (except in the genetically impaired conditions causing the deposition of the white adipose tissue (WAT)) [191]. However, both obesity caused by the genetic factors or due to the increased food intake and sedentary life style cause a low-grade systemic chronic inflammation that may lead to the development of type 2 diabetes mellitus (T2DM) and atherosclerosis [192–194]. The death of adipocyte serves as a major trigger for the recruitment of inflammatory LY6ChiCCR2+ monocytes and the accumulation of macrophages in the WAT as more than 90% of the macrophages in WAT are localized to the dead adipocytes [195, 196]. These macrophages then fuse to form syncytia sequestering and scavenging the residual "free" adipocyte lipid droplets and ultimately forming the multinucleate giant cells that serve as a hallmark of chronic inflammation. Furthermore, these macrophages recognize fatty acids (FAs) as potential inflammogens and reprogram themselves into classical macrophages (M1 macrophages) during obesity [104, 197, 198]. For example, saturated but not unsaturated fatty acids promote the inflammatory activation of macrophages via the activation of TLR4 as TLR4 is essential for high-fat diet-induced insulin resistance in adipose tissue and liver [199–203]. Additionally, Fetuin A (FetA or AHSG, a secreted glycoprotein) serves as an endogenous ligand for TLR4 for promoting the lipid-induced insulin resistance, lipotoxicity in β cells of the pancreas, and T2DM [204, 205]. However, M2 macrophages generated in the

environment promote the health of the WAT and the insulin sensitivity by an unknown mechanism in a lean state [206]. It can be hypothesized that the M2 macrophages via maintaining the health of adipocytes in WAT prevent the generation of signals including the death of adipose tissue that chemo-attract the proinflammatory monocytes reprogramming later into classical M1 macrophages. The genetic depletion of the M2 gene or M2 macrophages cause the induction of metabolic diseases upon high-fat-diet [206]. IL-6 promotes the generation of AAMs or M2 macrophages in adipose tissue environment during obesity [207]. The depletion of CD11b also increases the number of AAMs in adipose tissue during obesity and prevents the development of obesity-induced insulin resistance [208]. Thus targeting CD11b during obesity may prevent obesity-induced insulin resistance. Recently, a population of sympathetic neuron-associated macrophages (SAMs) has been identified controlling the obesity by engulfing and clearing norepinephrine (NE) [209].

#### 6. Conclusion and future perspective

Macrophages are innate immune cells that serve as a first line of defense against invading pathogens almost in every organ system including lungs, liver, intestine, kidneys, and brain. Along with acting as first line of defense against pathogens, PAMPs, DAMPs, and other xenobiotics they act as antigen presenting cells (APCs) and provide processed antigens to activate the adaptive immune response comprising of B and T cells. Thus macrophages are sentinel innate immune cells taking part in the generation of both acute and chronic inflammation induced during both sterile and infectious tissue damaging conditions via controlling the migration and activation of other innate immune cells including neutrophils and dendritic cells (DCs) as well as cells of the adaptive immune system. In addition to their role in controlling the process of inflammation they are also involved in the process of wound repair and regeneration, autoimmunity, obesity and associated insulin tolerance, angiogenesis and embryonic development of the fetus. Thus macrophage are the potent immunoregulatory cells of the innate immune system involved in host defense against infections and other inflammatory diseases including cancer and autoimmunity along with the maintenance of immune homeostasis involving the process of resolution phase during inflammation [210–212]. Hence macrophages are very important innate immune cells with immune regulatory function depending on their fine tuning or polarization during diverse inflammatory conditions as described here in the chapter.

Although macrophages have been discovered a century ago and revolutionized the immunology research and opened the road to the branch of immunology called innate immunity but much more is still remaining to explore in macrophage biology and their role in the regulation of development, homeostasis, immune homeostasis, inflammation, and disease pathogenesis. For example, macrophage immunometabolism and epigenetic mechanisms regulating their polarization and pro-and antiinflammatory phenotype and action have started to answer the several previously unknown questions that may influence the future immunotherapeutics and immunomodulatory approaches to target several immune-based diseases varying from autoimmune diseases to several cancers to metabolic diseases.

Macrophages: The Potent Immunoregulatory Innate Immune Cells DOI: http://dx.doi.org/10.5772/intechopen.88013
