**6. Role of dendritic cells in fungal infections**

Infections caused by opportunistic fungal pathogens include *Aspergillus fumigatus*, *Cryptococcus neoformans* and thermal dimorphic fungi (*Histoplasma capsulatum*, *Blastomyces dermatitidis*, *Paracoccidioides brasiliensis*, *Coccidioides immitis*, *Penicillium marneffei* and *Sporothrix schenckii*) and *Candida albicans*, the latter being a normal inhabitant of the human intestine, however as a pathogen has been associated with various serious diseases ranging from severe mucocutaneous allergy to bloodstream infections [144, 145].

DCs are the only ones capable of decoding information related to fungi [146]. The activation of the various immunity mechanisms is carried out efficiently by the DC that decode the signals sent by the fungi and translate them into an immune response of T helper (Th) *in vitro* and *in vivo* where the DC recognize each fungal morphotype of specific form by means of different recognition receptors which triggers the production and co-stimulation of cytokines [144]. For the immunological processes to be activated against different classes of fungi, the differentiation of the naive CD4 + T cells towards the Th1 or Th17 subtype is essential, which occurs by interaction with dendritic cells through different cytokines, these subsets of cells Th1 and Th17 play an important role in protection against various fungal diseases [147]. To be contained and resistant to fungal infections it is necessary that DC are activated since they produce cytokines of the IL-1 family, such as IL-1β and IL-18 and which activate other innate immune cells, or they modulate the development of the acquired immune response. IL-1β plays an important role in the inflammatory immune response and polarization of Th17 cells, whereas IL-18 participates in the differentiation of Th1 cells, but may also be responsible for the expansion of Th2 cells in the absence of IL-18 [148] IL-12 and IFN-γ promote Th1 differentiation, while TGF-β, IL-6, IL-1, IL-21 and IL-23 promote the differentiation and maintenance of Th17. The release of these cytokines by DCs is in turn regulated by innate receptors activated in response to fungal infection [149]. In order for the effective response of the host to the fungi to occur, the Th17 cells are indispensable [147].

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

Inflammatory DCs generate the responses of Th17 and Th2 antifungal cells *in vivo* by means of signaling pathways in which the TLR adapter MYD88 participates, while tolerogenic DCs promote regulatory differentiation programs of Th1 and Treg cells through processes in which the signaling adapter TRIF participates. In addition, STAT3, which alters the balance between the canonical and non-canonical activation of NF-κB and, therefore, the expression of the enzyme indoleamine 2,3-dioxygenase (IDO), has a key role to DCs plasticity and functional specialization. The multiple, functionally distinct receptor signaling pathways in DCs affect the balance between CD4+ effector T cells and Treg cells and, therefore, are likely to be harnessed by fungi to allow them to establish commensalism or infection [146]. In contrast some studies have shown that suppressive silencing of cytokine signaling 1 (SOCS1) can induce maturation of DCs and initiate the immune response find *C. albicans in vitro*. In which DC silenced by SOCS1 extend mouse survival and significantly decrease the colonization of fungi in the kidneys and the differentiation of CD4+ T cells producing IL-4 (Th2) or CD4+ T cells producing IL-17 (Th17 cells) are not affected under the same treatment, suggesting that DC silenced by SOCS1 significantly affect the CD4+ producer of IFN-γ cells (Th1). However, in the later stages of infection, when differentiation of Th1, Th2 and Th17 cells decreases in mice treated with DCs silenced with SOCS1, all serum cytokines (IFN-γ, IL-4 and IL-17) also reduced [150].

It has also been reported that NLRP3 linked with ASC and caspase 1, is triggering inflammation activated by pathogenic fungi such as *C. albicans*, *Aspergillus fumigatus* and *Cryptococcus neoformans*. Inflammasome NLRP3 responds to various stimuli, such as crystalline and particulate matter, extracellular ATP, pore-forming toxins, reactive oxygen species (ROS) (see **Figure 6**), endosome destabilization and cathepsin release, changes in intracellular calcium levels and K+ efflux [148].

Many types of cells, including macrophages and DCs, produce IL-1β induces the differentiation of Th17 cells, which are necessary for effective defense of the host against *C. albicans* when producing IL-17 through the stimulation of PRRs like Dectin-1 and Dectin 2, and both types of cells are indispensable for host defense against *C. albicans*. Dectin 1 is activated through the binding of the b-glucan of the fungal cells, and triggers intracellular signaling recruitment of Syk, activation of NF-kB *via* CARD9, the phosphorylation of IκB is mediated by the IκB kinase (IKK) complex, this complex consists of NF-κB essential modulator (NEMO, or IKKγ), IKKα, and IKKβ, to release the IκBα from NF-κB (see **Figure 6**). In the early stages of candidiasis, DCs are also essential in the antifungal response, since they are responsible for detecting fungal PAMP through their PRR, secreting cytokines and chemokines into the environment, retaining fungal particles by phagocytosis and presenting antigens to T cells to induce an adaptive immune response [147, 151].
