**5. Role of dendritic cells in bacterial infection**

Activated DCs are involved in the response to infections, which induces an increase in MHC expression, adhesion, and costimulatory molecules. The recognition of intracellular pathogens derived from mycobacterial cell wall components (lipids/glycolipids) such as phosphatidyl-myo-inositol mannoside, lipo-mannan, lipoarabinomannan, mycolic acids, lipopeptides, and phosphoinositol-containing lipids is given through the TLR-2, TLR-4, TLR-9, TLR-8 and the TLR1/TLR6 that heterodimerize with the TLR-2 [114, 115]. The signaling pathway that occurs in almost all TLRs is through MYD88, while for TLR4 the signaling pathway can be through MYD88 and TRIF [116, 117]. The activation of these receptors induces the activation of mitogen-activated protein kinase (MAPK) and NF-κB producing proinflammatory cytokines in DCs (see **Figure 5**). Other antigens derived from *Mycobacterium tuberculosis* such as lipoamide dehydrogenase C (Rv0462) induce the maturation and activation of DCs, increasing the expression of costimulatory molecules, MHC II and proinflammatory cytokines such as TNF-α, IL-1β, IL-6,

#### **Figure 5.**

*Role of DCs in bacterial infections. The TLRs are involved in the recognition of mycobacterial antigens. The activation of TLR-4 and TLR-2 by these antigens leads to an intracellular signaling pathway, leading to a Th1 and Th2 response, respectively. NOD-like receptors (NOD 1 and NOD 2) recognize bacterial peptidoglycans (DAP and MDP), the downstream signaling activates NF-*κ*B and MAPK generating a Th1 response. Description in the text (figure created by Muñoz-Carrillo* et al*., with BioRender.com).*

and IL-12, which leads to a Th1 immune response [118, 119]. Another protein that induces the maturation of DCs is RV2220 is a glutamine synthetase (GS) type I enzyme derived from M. tuberculosis, which induces the upregulation of MHC I and MHC II as well as CD80 and CD86, which leads to a Th1 response or Th2 or to regulatory T cell, through the secretion of cytokines such as, TNF-α, IL-6, IL-1β, IL-12 or IL-10, activating the MAPK and NF-κB pathway [120]. Different proteins that derive from *M. tuberculosis* trigger different responses, as cell wall-associated/ secretory Rv1917c antigen acts as a ligand of TLR-2, which induces the maturation of DCs secreting IL-10 and inducing the production of IL-4, IL-5 and IL-10 in CD4+ T cell which leads to a Th2 response (see **Figure 5**) [121].

On the other hand, DCs infection with other bacteria of the type *Listeria monocytoges*, *Shigella flexneri*, *Salmonella typhimurium* and *Francisella tularensis*, can activate inflammasome receptors [122]. The inflammasome is a multiprotein complex that contains one or more Nod-like receptors (NLRs) and regulates caspase-1 activity [123, 124], this complex is formed by at least three elements: (1) an inflammatory caspase (caspase-1, caspase- 11); (2) an adapter molecule such as apoptosis-associated speck-like protein containing a CARD, caspase recruitment domain (ASC); and (3) a sensor protein such as NLR Family Pyrin Domain Containing 1 (NLRP1), NLRP3, NLRP12, NAIP1, NAIP2, NAIP5, or absent in melanoma 2 (AIM2) [125]. The NLRP1 inflammasome is activated by anthrax lethal toxin, a toxin produced by *Bacillus anthracis* [126]. The toxin is composed of a protective antigen and lethal factor, the protective antigen generates pores in the membrane of the host while the lethal factor enters the cell and short NLRP1b and leads to inflammasome activation [127]. The NLRP3 inflammasome is activated by ligands derived from pathogens such as microbial cell wall components, nucleic acids, and pore-forming toxins [128]. Activation NLRP3 inflammasome require two signals: the priming which occurs when cells are activated by a PRR and activates the NF-kB, that induce the production of NLPR3, pro-IL-1β and pro-IL-18 and cytokines proinflammatory drugs such as IL-6, IL-8 and TNF-α. Subsequently the second signal carrying the assembly for inflammasome activation of caspase-1 occurs, which gives rise to the production of

#### *Role of Dendritic Cells in Pathogen Infections: A Current Perspective DOI: http://dx.doi.org/10.5772/intechopen.95551*

IL-1β and IL-18 responsible for maintaining the inflammatory response [129]. The NLRC4 inflammasome is activated by the bacterial flagellar protein flagellin, as well as the Salmonella type III secretion system, this inflammasome does not interact directly with its activator, the NAIPs proteins do (NLR family), which recognize the ligands and induce activation of the NLRC4 inflammasome [130, 131]. The double chains of microbial DNA present in the cytosol are recognized by the AIM2 inflammasome, this receptor contributes to host defense when pathogens do not have ligands that stimulate PRRs such as flagellin and LPS, such as *Brucella spp* and *Francisella spp*. This receptor binds to DNA and oligomerizes with ASC to then form the caspase-1 activating inflammasome, which leads to the secretion of cytokines such as IL-1β and IL-18 [132]. The cytokines that are produced through the inflammasome not only contribute to the defense of the host against infections, they also induce a Th17 response, this differentiation is driven by IL-1β, and is regulated by the factors NF-κB, activator protein 1 (AP-1) or the signaling way of the MAPK [133]. After the binding of IL-1β to IL-1R, signaling occurs through MYD88 until activating NF-κB, which induces the production of proinflammatory cytokines leading to a Th17 phenotype, in this differentiation IL-1β synergizes with IL-6 which upregulates the master transcription factor of Th17 cells, such as STAT3, IRF4 and RAR-related orphan receptor gamma (RORγt) [134]. The Th17 response is a typical response that occurs against extracellular bacteria such as *Klebsiella pneumoniae*, *Bordetella pertussis*, or *Streptococcus pneumoniae* and is characterized by a vigorous response of neutrophils which is coordinated by the Th17 cells, an alteration in IL-17 signaling increases the susceptibility to infection of these bacteria [135]. Although the defense of the host against extracellular bacteria is considered mainly associated with the

#### **Figure 6.**

*Role of DCs in fungal infection. Antigens derived from fungi such as b-glucan which are recognized by Dectin-1, this leads to a downstream signaling pathway activating NF-kB producing IL-6 and IL-23 leading to a Th17 phenotype. The union of Dectin-1 whit b-glucan also leads to the activation of ROS, which can NLRP3 inflammasome assembly activating caspase-1 which cuts the pro-IL-1 and pro-IL-18 generating its active forms, which together with IL-23 activates the Th17 phenotype. Description in the text (figure created by Muñoz-Carrillo* et al*., with BioRender.com).*

Th17, some authors indicate that effective protection requires the synergism of Th1 and Th17 cells, as it is for *Bordetella perussis* that induces the production of IFN-γ in the phase maximum infection and decreases its expression as time passes reaching basal levels at 14 days post-infection, however the Th17 response is persistent and production of IL-17 remains high even when the infection has been eliminated [136].

Other receptors involved in the response to pathogens are NOD1 and NOD2 receptors make up the family of NOD-like receptors containing a CARD domain (NLRC) [137]. These receptors are highly expressed in DCs and act as intracellular PRRs that recognize bacterial peptidoglycans [138–140]. NOD1 mainly recognizes γ-D-Glu-meso-diaminopimelic acid (DAP) while NOD2 recognizes muramyl dipeptide (MDP) [141]. Once the activation of these receptors occur, the downstream signaling activates NFκB through the union of its CARD domain to the protein kinase RIP2, which in turn recruits IRAK2, TRAF6, TAK1 binding protein (TAB1) and transforming growth factor-β-activated kinase 1 (TAK1) to activate the IKK complex, these events result in the degradation of IκBα inhibitor which leads to the translocation of NFκB to the nucleus and induce the expression of proinflammatory mediators [142]. In addition to the NFκB pathway, the stimulation of NOD1 and NOD2 leads to the activation of MAP kinases p38, ERK, and JNK pathway *via* RIP2. This event facilitates the formation of a multiprotein complex called "Nodosome" that leads to the production of inflammatory and antimicrobial agents mediated by NFκB and MAPK (see **Figure 6**) [143].
