**3. Metabolic modulation of functions of tissue-specific resident macrophages**

Resident macrophages especially in adults are formed through self-renewal of progenitor cells i.e. progenitor stem cells formed during embryogenesis that were responsible for primitive hematopoiesis persist in adulthood in various tissues

*Immunometabolic Processes of Macrophages in Disease States DOI: http://dx.doi.org/10.5772/intechopen.109936*

though in smaller proportions [4]. These stem cells under the influence of factors such as colony stimulating factor-1 and IL-34 mediate activation of proliferation of stem cells to tissue macrophages dictated by transcription factors e.g. PU.1. Stem cell derived macrophages have differing transcriptional and gene expression profiles when compared to monocyte-derived macrophages [70]. They however, all perform similar functions depending on resident tissue and to which polarization end they are activated. Below is a discussion of some of tissue specific macrophages extensively studied and how they are metabolically programmed to function.

#### **3.1 Alveolar macrophages**

Alveolar macrophages are derived from fetal liver monocytes which during birth colonized the lungs and maintained self-perpetuation to adulthood. Primarily, their main function is to clear pulmonary surfactant that constantly being secreted into the alveolar space to maintain lung compliance [71]. Additionally, they also carry out immune surveillance and phagocytosis of foreign particles that have been inhaled [71]. Surfactants are predominately made up of lipids and as such, alveolar macrophages are metabolically equipped to handle lipid metabolism. During development, alveolar macrophages, under the influence of TGF-β and GM-CSF, activate the transcription factor PPARγ which regulates metabolism of fatty acids [72]. PPARγ activate genes responsible for increased fatty acid oxidation, esterification and efflux of cholesterol from cells [72]. Inability of alveolar macrophages to metabolize lipids leads to an accumulation of lung surfactant; a disease termed alveolar proteinosis [73]. Metabolically, alveolar macrophages conduct oxidation-phosphorylation reaction, fatty acid metabolism and cholesterol homeostasis.

#### **3.2 Interstitial macrophages**

Interstitial macrophages take residence in the space between epithelium and capillaries. They are derived from circulating blood monocytes and though are present in smaller numbers, their concentration increases in cases of immune response. Interstitial macrophages majorly junction as immune sentinels and once activated by a foreign particle, they differentiate to M1 phenotype [25]. Thus metabolically, interstitial cells conduct predominantly glycolysis and induction of nitric oxide synthase resulting in inhibition of mitochondrial oxidation-phosphorylation reaction [25].

#### **3.3 Liver macrophages**

Two types of liver macrophages have been documented: Kupffer cells and liver capsular macrophages [25]. Kupffer cells, located in the sinusoidal lumen, are derived from precursors of fetal liver monocytes and are capable of renewal. They carry out three major functions: clearance of damaged erythrocytes, immunological tolerance, clearance of blood-borne antigens [74]. In the presence of an antigen, Kupffer cells shift cellular metabolism towards glycolysis. This leads to increased glucose uptake and subsequently secretion of interleukin 10 [75]. Liver capsular macrophages on the other hand apart from performing immune surveillance, they also participate in neutrophil recruitment during an inflammatory episode. Less predominantly, liver macrophages conduct iron metabolism which is a major function of splenic macrophages [25]. During differentiation of Kupffer cells, notch ligands from endothelial cells of liver sinusoids induces expression of Spi-C. the latter is involved in activating genes that are responsible for iron metabolism 74].

### **3.4 Microglia**

Microglia are CNS macrophages derived from embryonic yolk sac. They function to surveil the brain for pathogens, regulate neurogenesis and synaptic activity and have a role in clearance of apoptotic cells. Notably, microglia are active conductors of oxidative phosphorylation in inactive states to meet their energy requirement [76]. However, upon activation, they shift to a glycolytic model similar to that of blood monocyte derived macrophages. The metabolic profile of microglia is highly dynamic in nature and largely being influenced by the environment [76]. In steady state homeostatic conditions, microglia utilize oxidative phosphorylation for energy production; however, in hypoglycemic conditions, they switch to glutamine metabolism to support energy production [25].

#### **3.5 Osteoclasts**

Osteoclasts are multinucleated terminally differentiated monocyte-derived macrophages that are majorly found in the bone marrow. Predominantly, their function is bone resorption which they conduct via dissolution of collagen and mineral it the bone matrix [25]. This process is highly energy deficient thus osteoclasts have mitochondria not only in great numbers but size and complexity [25]. Formation of new osteoclasts is dependent on the factors RANK and osteoprotegerin. Activation of these systems is highly dependent on oxidative phosphorylation and mitochondrial biogenesis thus hypoxic conditions limit osteoclastogenesis process. Additionally, the metabolic profile of osteoclasts consists of elevate fatty acid oxidation, glutaminolysis, decreased glycolysis and activity of pentose phosphate pathway [77]. The former two serve to fuel oxidative phosphorylation processes which is required to produce energy for the energy driven process of bone resorption. Lactate, the end product of glycolysis has been shown to inhibit the osteoclastogenesis process [77]. During bone absorption by osteoclast, the metabolically switch to glycolysis.

#### **3.6 Peritoneal macrophages**

Two types of macrophages populate the peritoneum: large peritoneal macrophage (LPM) and small peritoneal macrophage. The former is derived from yolk sac progenitors with self-renewal capability thus forming the resident macrophages [25]. They function to phagocytose dead cells and bacteria. Small peritoneal macrophages are derived from circulating blood monocytes and predominantly function as immune sentinels, regulate immune response. In normal health conditions large peritoneal macrophages are more than small peritoneal macrophages but status changes often during immune stimulation or an ongoing inflammatory condition. Metabolically, Large peritoneal macrophages upon inflammatory stimulation exhibit increased activity in the mitochondria and electron transport chain which is linked to production of mtROS [78]. This high oxidative metabolism is fueled by fatty acids and glutamine whereby stimulated LPMs incorporate mitochondria into the phagosome and ensuing glutaminolysis induces complex II of the electron transport chain [78]. Notably, genes involved in lipid metabolism such as PPARγare downregulated in LPMS. SPMs on the other hand have higher glycolytic activity with reduced fatty acid oxidation and oxidative phosphorylation [78]. Stimulation of SPMs activates NF-kB which is associated with production of inflammatory cytokines.
