**1. Introduction**

Obesity results from an energetic balance alteration caused by the abnormal or excessive accumulation of triglycerides in the adipose tissue (AT). It is a chronic and multifactorial ailment and is considered a serious public health illness. Its prevalence is on the rise, and the World Health Organization (WHO) estimates that since 1975, obesity has increased almost thrice worldwide, reaching epidemic proportions. It is considered the epidemic of the twenty-first century [1–3].

The body mass index (BMI) is the most accepted parameter to determine clinically overweight and obesity and is frequently used to identify overweight and obesity in adults using the relationship between weight and stature. It is calculated by dividing the person's weight in kilograms by his/her squared stature in meters (kg/m2 ).

The WHO defines overweight and obesity for adults as follows:


Although the BMI is not an ideal indicator because it does not allow the exact determination of an individual's adiposity, it is the most recommended for clinical use by international health organizations due to its easy usage [4].

Different diseases are associated with obesity because there are alterations in the immune response generated by an inflammatory process, which is also related to the following:


### **2. Inflammation and obesity**

The AT can be classified into different compartments: subcutaneous tissue and visceral adipose tissue (VAT). In obesity, VAT is highly associated with the increment of cardiovascular risk and the development of MetS, hypertension, insulin resistance, and T2DM [6].

The VAT is composed of a greater number of adipocytes, but it is a tissue with plentiful immune infiltrate with the presence of eosinophils, neutrophils, macrophages, regulatory T lymphocytes (Treg), CD4+ T lymphocytes, CD8+ T lymphocytes, and type 2 innate lymphoid cells (ILC2). In the VAT in homeostasis, there is a microenvironment rich in IL-4, IL-5, and IL-13, as well as the presence of Treg cells, eosinophils, and ILC2 that promote a Th2 phenotype and M2 macrophage polarization, which express arginase-1 (ARG-1) that inhibits the activity of the inducible enzyme nitric oxide synthase (iNOS) and increase IL-10 production. In obesity, the adipocyte's number and size are increased due to the accumulation of fatty acids inside the cells. This fact demands a higher oxygen concentration, and if it is not attained, it favors the adipocytes' death by apoptosis. That, in turn, causes alterations in the tissue's number and type of immune cells [1, 7–10].

One of the populations that are diminished under the above-described situation is the Treg lymphocytes, which depend on the presence of IL-33 and the nuclear factor PPAR-gamma. In normal conditions, these lymphocytes produce large amounts of IL-10, but when these cells decrease in number, the amount of tumor necrosis factor alpha (TNF alpha), IL-6, and RANTES (CCL5) increases [11]. There is also a mobilization of macrophages into the AT to eliminate dead cells and "remove" their lipid content. These increase the presence of inflammation mediators in the tissue as most of the macrophages change from an M2 phenotype to an M1, which promotes the secretion of proinflammatory cytokines (TNF alpha, IL-6, and IL-12). Other cellular subpopulations (CD8+ T lymphocytes, Th1 CD4+ lymphocytes, B-lymphocytes, and granulocytes) are also activated and secrete cytokines such as TNF alpha, interferon (IFN) gamma, and IL-6, which also contribute to the amplification of the inflammatory response (**Figure 1**) [12–14]. In this way, the increase of these mediators is relevant during the adaptation process

*Phagocytosis: Inflammation-Obesity Relationship DOI: http://dx.doi.org/10.5772/intechopen.110510*

#### **Figure 1.**

*Adipose tissue in homeostasis and obesity. The adipose tissue (AT) is infiltrated by diverse immune cells that communicate with each other. In homeostatic conditions, the cells present in the tissue include eosinophils (Eo) and neutrophils (Nt), which secrete IL-4 and IL-3; regulatory T lymphocytes (Treg), which produce IL-10; Natural Killers (Nk), which release IL-13; and adipocytes, which release adiponectin. Together, these cytokines generate an anti-inflammatory Th2 microenvironment, and macrophages (Mo) polarize towards an M2 phenotype characterized by the transcription factors STAT-6 and PPAR. In obesity and hyperglycemic states, AT adipocytes undergo hypoxia and cell damage, leading to apoptosis and the release of damage-associated molecular patterns (DAMPs). Moreover, leptin expression increases in obesity, shifting the Mo phenotype towards an inflammatory profile (M1) and increasing transcription factor NFκB. Mo counteract DAMPs through the phagocytosis of apoptotic adipocytes, thereby transforming into foam cells (FC), which are associated with metabolic complications. Upon activation, the cells of this microenvironment secrete more proinflammatory cytokines like TNFα and IL-1β, which, in the long term, decrease insulin production and damage pancreatic β-cells. Higher levels of IL-6 and Nt elastase (NE) produce systemic insulin resistance, and higher IL-8 increases Nt infiltration, further increasing inflammation. Finally, the excess of proinflammatory cytokines, along with the increase in LDL and FFAs, damage the vascular endothelium, increasing the expression of adhesion molecules and the deposition of foam cells that cause atherosclerosis and other pathologies. Created with BioRender.com.*

to the gain in fat mass [15]. Nevertheless, when this inflammatory process is not resolved, chronic obesity ensues, which leads to tissue fibrosis and discharge of the extracellular matrix, which prevents the adipocyte enlargement and storing of lipids with the consequent liberation of fatty acids that increase the inflammatory process associated with the loss of insulin sensitivity. These alterations help to the establishment of a state of low-degree chronic inflammation characteristic of individuals with obesity [16].

### **3. Insulin resistance, metabolic syndrome, and type 2 diabetes**

Insulin is a hormone secreted by the pancreatic beta cell in response to diverse stimuli, glucose being the most relevant. Its principal function is to maintain glycemic homeostasis. In this way, after each meal, insulin suppresses the liberation of fatty acids while favoring triglyceride synthesis in the adipose tissue [17].

Insulin resistance (IR) refers to a state in which cells do not respond normally to insulin, and thus, glucose cannot enter the cells with the same easiness, causing its accumulation in the blood (hyperglycemia) [18].

The changes happening in the VAT that lead to the liberation of proinflammatory mediators promote insulin resistance by interfering with insulin signaling through the activation of the c-JUN N-terminal kinase (JNK) and the nuclear factor kappa B (NFkB) at a local level (AT and macrophages). When these mediators escape into circulation and reach the insulin target tissues (skeletal muscle and the liver), they unchain a systemic IR diminishing the insulin effect in these organs. This process precedes the development of metabolic diseases such as MetS [19–21].

MetS has been defined as a clinical entity characterized by a combination of risk factors. Individuals suffering from this disease show a metabolic disorder that includes visceral obesity and some of the following alterations: IR, triglycerides increase, high-density lipoproteins (HDL-C) decrease, hypertension, and hyperglycemia. This pathology confers a high risk of suffering from T2DM or cardiovascular diseases [8, 22].

Diabetes mellitus is an endocrine-metabolic disease characterized by raised blood glucose levels or hyperglycemia caused by deficient insulin secretion or action. Evidently, the most severe consequence is the damage caused to beta cells caused by lipotoxicity. The excessive accumulation of triglycerides in the pancreatic islets increases the expression of iNOS, raising nitric oxide (NO) levels, which causes alterations in the beta cells function and, finally, apoptosis of these cells, which gradually lose their capacity to compensate for IR with higher insulin secretion. Glucose blood levels increase progressively in prediabetic stages first, leading finally to T2DM [23].

### **4. Phagocytosis general aspects**

The phagocytosis process includes several sequential stages, which are common to macrophages and neutrophils that comprise chemotaxis, adhesion, endocytosis, and the intracellular physical and biochemical changes that prepare the phagocytes to ingest, kill, and digest microorganisms: increment in the cell's general metabolism, phagosome formation, the interaction of the phagosome with endosomes and lysosomes to form the mature phagosome (phagolysosome), phagolysosome acidification, generation of reactive oxygen and nitrogen intermediates, activation of lysosomal hydrolases, and, finally, the elimination of waste materials through exocytosis.

#### **4.1 Chemotaxis**

An infection or trauma situation favors a tissue microenvironment, which gives rise to the formation of materials, both exogenous (microorganism derived) and endogenous (coming from damaged tissue), with chemotactic activity. In order for the phagocytic cells to go to the injury site, they must come out of the blood vessels, which involves the participation of adhesion molecules both in phagocytic (integrins and selectins) and endothelial (selectins and adhesins) cells. Some of these molecules are constitutive of the cellular membrane, while others are induced by chemotactic factors or some cytokines. Cells come out of the blood vessels by diapedesis, attracted by factors with chemotactic activity [24, 25].

Chemotaxis requires energy in the form of adenosine triphosphate (ATP) and the presence of calcium and magnesium, which indicates that it is an active metabolical

#### *Phagocytosis: Inflammation-Obesity Relationship DOI: http://dx.doi.org/10.5772/intechopen.110510*

process. As with all cellular functions that imply mobility, chemotaxis depends on the function of contractile structures of the cells that constitute the cytoskeleton.

The interaction of the cells with their external ligand occurs through membrane receptors, which generate biochemical signals that activate several G proteins and protein kinases that result in the polymerization of actin with the consequent cell movement (chemotaxis and phagocytosis) [26].

#### **4.2 Opsonization**

Opsonization improves the endocytosis process and requires the interaction of the ingestible particles with serum factors called opsonins. These include antibodies (usually IgG), complement components (C3b, C4b, or iC3b), and other proteins present in the serum, such as colectins and C reactive protein. Opsonins promote phagocytosis through specific receptors against them on the membranes of phagocytic cells [27, 28].

#### **4.3 Endocytosis**

Endocytosis is a process by which particles enter the cells due to the presence of receptors on the surface of the phagocytes. These receptors can be pathogen recognition receptors (PRR), which recognize components that are unique to microorganisms or receptors for opsonins.

The cross-linking of receptors for the immunoglobulin Fc region gives rise to signals with the participation of protein kinases, GTPase, ATPase, adaptor proteins, and other associated proteins that lead to actin polymerization, endocytosis, and cellular movement [29].

Among the PRRs, we can consider the Toll-like receptors (TLRs), which have an intracytoplasmic domain and are able to transmit signals. Ten TLRs have been identified, and although there are cellular activation pathways depending on the involved TLR, the mechanism representative of the events is described as follows:

The interaction of TLR with its ligand promotes the recruitment of the signal adaptors MyD88, a protein associated with the intracellular receptor called Toll/IL-1 (TIR) and the adaptor molecule that contains TIR (TRAM) or TIR domain-containing adaptor molecule inducing interferon-beta (TRIF). These events occur in the TIR domain of the TLRs. Depending on the type of adaptor involved, this binds to the interleukin 1 receptor-associated kinases (IRAKs) are a family of related signaling intermediates (IRAK1, IRAK2, IRAK4), TANK-binding kinase (TBK) 1 and an IkappaB kinase (IKK)-related kinase epsilon, which, in turn, binds to the TNF-6 receptor-associated factor (TRAF-6), which becomes activated and stimulates TAK1. This kinase sets in motion the Mitogen-activated protein kinase (MAPK) kinase protein signalization that phosphorylates other kinases such as JNK, which activates and translocates nuclear factors such as PA-1 and NF-κB, with the consequent transcription of the genes coding for proinflammatory cytokines. The importance of the TLRs lies in the fact that if there are defects in signalization, there will be high susceptibility to infections [30].

Within the metabolic changes associated with endocytosis, we can mention that in the phagocytic cells, as a result of the interaction with the ingestible particle, a series of events occur associated with the morphological and biochemical changes that include engulfment of the particle, formation of the digestive vacuole, and lysosomal degranulation with the release of enzymes and other components inside the vacuole.

The morphological events associated with vacuolization and degranulation are similar both in neutrophils and in macrophages, except for the following differences: macrophages can synthesize more granules in their Golgi complex, they can get rid of the microorganisms' remains by exocytosis, and, finally, they survive the phagocytosis process, while neutrophils generally die [31].

#### **4.4 Phagocytosis events and microbicidal activity**

A few seconds after the interaction of the phagocytic cell with chemotactic agents and microorganisms, biochemical alterations are generated, which indicate the presence of metabolic changes related to membrane potential, production and release of cyclic adenosine monophosphate, release of superoxide anion, and later escape of several lysosomal enzymes. Some of these metabolic changes are related to oxygen and nitrogen metabolism, while others are of a nonoxidative nature.

Among the nonoxidative changes accompanying the endocytosis process, we can find an increment in oxygen and glucose consumption and an increase in the activity of the pentose or hexose monophosphates cycle; there is also superoxide anion and hydrogen peroxide production. The set of these changes is what is known as the "respiratory burst" [32].

The destruction of microorganisms occurs through these mechanisms, both oxygen-dependent and independent. The former includes the participation of radicals generated by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, which transforms molecular oxygen into superoxide anion, which, in turn, is transformed into hydrogen peroxide and then into hydroxyl radicals, which, along with the oxygen singlets, constitute the reactive oxygen intermediates (ROIs). The enzymatic system that catalyzes these oxidative changes is named "NADPH oxidase." In neutrophils, the microbicidal activity is increased by the myeloperoxidase that uses hydrogen peroxide as the substrate to produce, along with halide, highly toxic compounds [33].

Nitric oxide (NO) is generated in macrophages from the L-arginine metabolism; generally, its production is regulated by the effects of some cytokines such as gamma interferon. Given its unstable nature and in the same way as the ROI, NO interacts avidly with various chemical groups present in many molecules, causing functional and structural alterations and molecular breakdowns in them. In the target cells, NO inhibits DNA synthesis and respiratory activity [31].

Oxygen-independent mechanisms include lysosomal enzymes that intervene in the digestion of severely damaged microorganisms, and proteins with microbicidal activity. Cathepsin B, cathepsin D, glucuronidase, mannosidase, and phosphatase A2 are acid hydrolases; elastase, cathepsin G, proteinase 3, and collagenase are neutral proteases; and myeloperoxidase, lysozymes, defensins, and lactoferrin are microbicidal factors. Lysosomal hydrolases are activated by the acidification of the phagosomal environment through the activity of an endosomal enzymatic system that functions as a proton pump called "Proton ATPase," which is incorporated into the digestive vacuole's membrane when the phago-endosomal fusion occurs [34, 35].
