**1. Introduction**

#### **1.1 Macrophages: innate and adaptive immunity**

Macrophages are present as crucial members of a multitude of specialized cells that fortify our immune system by fighting against infection caused by pathogens [1]. Macrophages differentiate from tissue-infiltrated circulating monocytes, which originate from bone marrow resident myeloid precursors [2, 3]. All tissue macrophages, however, do not originate from monocytes. Although some macrophage origins have been studied carefully, the detailed molecular mechanisms toward the differentiation of different macrophage types remain mostly uncharacterized [4–7]. Irrespective of their origin, most macrophages eliminate encountered pathogens through phagocytosis (element of innate immunity) and additionally present the foreign antigens derived from pathogens via major histocompatibility complex (MHC) molecules to lymphocytes leading to lymphocyte activation (element of adaptive immunity) [2, 8]. Cytoskeletal modulations and transcriptional activation programs intrinsically associated with macrophage-mediated immune functions (e.g. phagocytosis, autophagy/xenophagy) conform to the in-built maneuvering of macrophages as they confront with different kinds of pathogens. Several lines of

evidence substantiate that Wnt signaling is important for the transcriptional programs and cytoskeletal modulations inherent to macrophages during immune surveillance and response to different kinds of infection [9–13].

#### **1.2 Wnt signaling**

Wnt signaling is an integral theme of tissue/organ morphogenesis, repair, and maintenance. Thus, it is not surprising that this central premise of life is also an important component of macrophage function [9–16]. Wnts constitute a large family of secreted glycoprotein ligands, which bind to Frizzled and/or ROR cell surface receptors during various phases of tissue and organ development, morphogenesis, and homeostasis. Frizzleds are seven transmembrane-spanning receptors bearing homology to heterotrimeric G protein-coupled receptors, and RORs bear homology to tyrosine kinase receptors [17–20]. Based on the gene database, there are about 19 Wnt ligands and about 12 and 2 Frizzled and ROR receptors, respectively [21, 22]. Whether all these gene products are expressed and functional in our system in different cellular contexts is unclear at this stage. Although there is evidence of co-receptor function by the ROR subtype receptors during Wnt-Frizzled signaling [22, 23], the degrees of coordination between the Frizzled and ROR receptors under different physiological conditions are yet to be characterized at the molecular level. Given the considerable homology among the respective members of the Wnt and Frizzled families, any one Wnt ligand may interact with multiple Frizzled receptors. Thus, the outcome of Wnt-Frizzled signaling in a particular cell type under a certain condition could be dependent precisely on the existing profile of Wnt-Frizzled stoichiometry [20].

Wnt signaling is broadly classified into two types—canonical or β-catenindependant and noncanonical or β-catenin-independent (**Figure 1**). The transcriptional coactivator β-catenin promotes gene expression by LEF/TCF family transcription factors in response to canonical Wnt signaling, and transcriptional activators such as NFκB, NFAT, and AP1 are associated with noncanonical Wnt signaling. Even though the ligands Wnt3A and Wnt5A are mostly considered as representatives of the canonical and noncanonical modes of Wnt signaling, respectively [21, 24], the mode of signaling is in reality governed by the receptor(s) receiving the Wnt signal as mentioned above and the associated adaptor molecule(s) transmitting it. Thus, some level of crosstalk between the two modes of signaling would not be uncommon. Interestingly, the intracellular adaptor molecule Disheveled acts as a mediator of both β-catenin-dependant and β-catenin-independent Wnt signaling. Heterotrimeric G proteins, which have been reported to couple with Frizzled receptors, add to the complexity of Wnt signaling [18, 25]. Whether heterotrimeric G proteins cooperate with Disheveled during canonical and noncanonical Wnt signaling is not known clearly. Although there is some evidence of the involvement of lipid molecules such as cholesterol in switching Disheveled between the canonical and noncanonical modes of Wnt signaling [25], the molecular details of such presumed conformational switches remain largely undefined. The reason behind the preference of cell surface coactivator receptors such as lipoprotein receptorlike protein (LRP) 5/6 for the canonical mode of Wnt signaling as opposed to the noncanonical mode also remains unclear (**Figure 1**).

#### **1.3 Wnt signaling in immune system**

Given that host cytoskeletal rearrangements encompassing phagocytosis and autophagy/xenophagy and transcriptional regulation of immune defense genes

*Wnt Signaling Regulates Macrophage Mediated Immune Response to Pathogens DOI: http://dx.doi.org/10.5772/intechopen.86433*

#### **Figure 1.**

*An overview of Wnt signaling cascade: in canonical mode of signaling, the association of Wnt-Fz and LRP activates a signaling cascade through Dvl and/or G-proteins that leads to inactivation of a GSK3 associated destruction complex which in the absence of Wnt would phosphorylate β-catenin for terminal destruction by proteasome. Via GSK3 inactivation, β-catenin gets stabilized and translocates to the nucleus where it acts as a co-activator of LEF/TCF (transcription factor). In the non-canonical mode of Wnt signaling (often β-catenin independent) the signaling cascade through Dvl and/or G-protiens leads to activation of Ca2+ mediated signaling where protein kinase C (PKC) and CaMKII gets activated and leads to translocation of NFκB, NFAT to the nucleus. Wnt also binds to ROR leading to activation of AP1. A crosstalk between the pathways is not uncommon.*

come into the direct line of control of pathogenic incursions and immune homeostasis [9–12, 26], Wnt signaling aptly associates with host-pathogen interactions of macrophages at the crossroads of innate and adaptive immunity. The attributes of Wnt signaling and the microbe world being diverse, their mutual interactions in the various host defense programs are expected to be manifold. Although Wnt3A and Wnt5A are often represented as the prototypes for the two different modes of Wnt signaling (canonical and noncanonical) in the regulation of immune response, several molecular details of the balancing act of the Wnts in relation to the interactions of macrophages with different microbes remain unclear.

The primary objective of this chapter is to briefly summarize the conceptual advancement in the context of Wnt signaling and immune defense by macrophages, focusing mainly on transcriptional activation and the actin cytoskeletonassociated phagocytosis and autophagy machineries. Our aim is to also address unanswered questions, which may prove instrumental in bridging existing gaps in our evaluation of the Wnts in the context of macrophage host defense programs.
