*2.1.1 Cellular component*

Neutrophil granulocytes are normally found in the bloodstream. During the acute phase of inflammation, they are among the first inflammatory cells migrating from blood vessels to the inflamed site, recruited by chemical signals such as interleukin-8 (IL-8), through a process called chemotaxis. Similarly, monocytes migrate from the bloodstream to tissues in response to chemokine release at infection sites, become

### *Immune System, Gut Microbiota and Diet: An Interesting and Emerging Trialogue DOI: http://dx.doi.org/10.5772/intechopen.104121*

activated, and differentiate into macrophages. Macrophages constitute, together with neutrophils, the largest group of cells endowed with phagocytic activity, they carry out their defense action by surrounding foreign microorganisms with pseudopodia, i.e., extroversions of the plasma membrane, forming the phagosome. The phagosome then merges with the numerous granules present in the cytoplasm, containing various compounds toxic for microorganisms, such as defensins, cathelicidins, lysozyme, and lactoferrin, forming the phagolysosome. Alternatively, the so-called respiratory or oxidative burst is activated, resulting in the formation of reactive oxygen species finally producing hypochlorite, hypobromite, and hypoiodite that kill microorganisms. In addition to the phagocytic function, macrophages are also responsible for the processing and presentation of antigens to T cells, as mentioned above [7]. Natural killer (NK) cells eliminate virus-infected and tumor cells through a cytotoxic activity, mediated by perforin-containing granules and granzymes. The former form pores in the plasma membrane and the latter, entering through these pores, induce the caspase cascade, leading to apoptosis of target cells. NK cells can also kill target cells through another mechanism, referred to as antibody-dependent cellular cytotoxicity (ADCC), in which NKs recognize target cells to which IgG has been previously bound [7, 8]. Many cells of the innate immune system are activated through receptors expressed on their membrane, namely pattern recognition receptors (PRR), with a long evolutionary history, which are able to recognize conserved structural patterns expressed by microorganisms, such as the microbe- and pathogen- associated molecular patterns (MAMP and PAMP, respectively). In particular, the type of PRR recognizing MAMP and PAMP is represented by the toll-like receptors (TLRs), a family of transmembrane proteins primarily expressed on the surface of immunocompetent cells, i.e., monocytes, macrophages, and dendritic cells, but also on intestinal epithelial cells. When a TLR recognizes a MAMP, a complex protein signal transduction cascade is triggered generating the appropriate immune response for that microorganism [9]. In most cases, the inflammatory response activated by TLRs leads to the activation of the nuclear factor-kappaB (NF-κB), which induces the transcription of numerous pro-inflammatory genes, including IL-8 [10]. TLRs can also be activated by endogenous danger signals such as the damage-associated molecular patterns (DAMP), molecules that are released in the intracellular or extracellular space following tissue injury, cellular stress, or apoptosis. Some innate responses can activate the inflammasome, a multiprotein complex resident in the cytosol as an inactive form, particularly in macrophages. A 2-hit-theory has been postulated, stating that for inflammasome activation two distinct signals are required. The first signal, triggered by PAMPs or DAMPs, activates the TLR signaling cascade, leading to the expression of some pro-inflammatory cytokines in an inactive form, such as proIL-1β and proIL-18. The second stimulus activates the inflammasome and generates caspase-1. Only thereafter proIL-1β and pro-IL-18 are cleaved by caspase-1 to mature IL-1β and IL-18, which can be secreted by macrophages and promote the inflammatory response [11]. Dendritic cells (DCs) are specialized to "sample" the entry sites of potential infectious agents, so they are found as immature cells in nonlymphoid tissues where antigens can be encountered, such as skin and other mucosal sites. The antigen recognition, through TLRs' activation, initiates the maturation process of DCs, which are induced to secrete various pro-inflammatory cytokines. After the encountering, the antigen is internalized through phagocytosis or pinocytosis and processed by the DCs, which migrate to secondary lymphoid organs (lymph nodes, spleen), where the exposed antigens are presented to populations of T lymphocytes, both naive and memory cells [6]. Mast cells and basophil granulocytes, similarly to monocytes, circulate in the

blood as immature progenitor cells, differentiating into mature cells in different tissues in response to cytokine secretion. Mast cells and basophils are particularly found in association with blood vessels and nerves, in close proximity to mucosal surfaces that interface with the external environment, where they are able to detect infectious agents through TLRs. Upon activation, mast cells and basophils immediately extrude histamine from granules and, within a few minutes, release lipid mediators (such as prostaglandins, leukotrienes, and thromboxane), promoting vascular permeability, vasodilation, and rapid recruitment of eosinophils, neutrophils, and other immune cells [7]. Eosinophils are another type of circulating granulocytes that can be recruited to sites of inflammatory reactions, where their numbers can be 100-fold higher than in the blood. When activated, eosinophils release the contents of their granules (numerous enzymes, major basic protein, eosinophilic cationic protein), which act primarily on extracellular helminthic parasites. Eosinophils also actively participate in allergic diseases [8]. Innate lymphoid cells (ILCs), although lacking antigen-specific receptors, play an important role in the inflammatory response and the maintenance of immune homeostasis, particularly in mucosal tissues. Based on their phenotypic and functional features, ILCs have been grouped into three major subsets. Among them, group 3 ILC (ILC3) are implicated in intestinal homeostasis as they produce IL-22, a key regulator of the intestinal barrier [12]. Recent studies have shown that some myeloid cells of the innate immune system, essentially macrophages and NK cells, can develop a nonspecific immunological memory, i.e., these cells, after a first stimulus, acquire the ability to respond effectively to a subsequent stimulus, different from the first. Effector stimuli for such "innate memory" are represented by various components of bacteria or fungi, such as lipopolysaccharide (LPS) or β-glucans, as well as viruses, and such innate memory is called "trained immunity" [13]. Following activation, the cells involved in this phenomenon undergo processes of chromatin unfolding, which thus becomes more accessible for gene transcription. These processes, globally referred to as "epigenetic reprogramming," include methylations, acetylations, and phosphorylations at specific chromatin sites. The activation of gene transcription following the first stimulus is therefore accompanied by the acquisition of specific "epigenetic profiles," which are only partially lost after the elimination of the stimulus. In this way, a kind of nonspecific "memory" is developed, which makes some innate immune cells more easily and rapidly activated, following a subsequent heterologous stimulus. Trained immunity has gained increasing scientific relevance in recent years, for the hypothesis that previous infections can induce a metabolic and epigenetic reprogramming of some cells of innate immunity, leading to an improved defense response during subsequent infections of various types, at the same time trained immunity could also be negatively involved in hyperactivation of the immune system leading to chronic inflammation, as in atherosclerosis [14].

### *2.1.2 Humoral component*

The complement system represents a set of plasma and membrane proteins endowed with enzymatic activity that can result in direct lysis of the foreign agent. These proteins circulate in the blood as functionally inactive molecules, called components. Complement activation occurs by cascade mechanism events, leading to sequential activation of the various inactive components. There are distinct pathways of complement activation: classical (activated by antigen–antibody binding), alternative, and lectinic, which are triggered by different mechanisms, but then converge in a common pathway leading to the formation of the membrane attack complex, which, by binding to the microorganism membranes, determines their osmotic lysis, through the formation of pores on the membrane itself [7].
