Wnt/TLR Dialog in Neuroinflammation, Relevance in Alzheimer's Disease

Abstract

The innate immune system (IIS) represents the first line of defense against exogenous and endogenous harmful stimuli. Different types of pathogens and diverse molecules can activate the IIS via a ligand-receptor mechanism. Cytokine release, recruitment of immunocompetent cells, and inflammation constitute the initial steps in an IIS-mediated response. While balanced IIS activity can resolve a harmful event, an altered response, such as deficient or persistent IIS activity, will have a critical effect on organism homeostasis. In this regard, chronic IIS activation has been associated with a wide range of diseases, including chronic inflammatory disorders (inflammatory bowel disease, arthritis, chronic obstructive pulmonary disease, among others), cancer and, more recently, neurodegenerative disorders. The relevance of the immune response, particularly inflammation, in the context of neurodegeneration has motivated rigorous research focused on unveiling the mechanisms underlying this response. Knowledge regarding the molecular hallmarks of the innate immune response and understanding signaling pathway cross talk are critical for developing new therapeutic strategies aimed at modulating the neuroinflammatory response within the brain. In the present review, we discuss the IIS in the central nervous system, particularly the cross talk between the toll-like receptor-signaling cascade and the wingless-related MMTV integration site (Wnt) signaling pathway and its relevance in neurodegenerative disorders such as Alzheimer's disease.

Keywords: Alzheimer’s disease; Wnt signaling; immune response; neuroinflammation; toll-like receptors.

Figure 1

TLR molecular cascade. Upon activation, TLRs can signal through different transduction molecules. The MyD88-mediated pathway constitutes the classical TLR signaling pathway and ultimately leads to the activation of the NF-κB transcription factor, resulting in the production and release of pro-inflammatory mediators. In addition, some members of the TLR family can activate other pathways, such as PI3K and JAK/STAT. Although these mechanisms also lead to NF-κB activation, the intermediary molecular nodes can interact and activate additional signaling pathways. TLR, toll-like receptor; MyD88, myeloid differentiation factor 88; TAK1, transforming growth factor-β-activated kinase-1; IKK, inhibitory NF-κB kinases; NLK, nemo-like kinase; JNK, c-Jun N-terminal kinases; NF-κB, nuclear factor-κB; TRIF, TIR-containing adaptor inducing interferon-β; PI3K, phosphatidylinositide-3 kinase; Akt, protein kinase B; GSK3β, glycogen synthase kinase 3 β; JAK, Janus kinase; STAT, signal transducer and activator of transcription.

Figure 2

General overview of the Wnt signaling pathway. The Wnt signaling pathway can be divided into the canonical Wnt signaling and non-canonical Wnt pathways. During activation, canonical Wnt ligands interact with the Fz-LRP5/6 complex receptor, inducing the activation of Dvl and the recruitment of Axin by LRP5/6. This situation leads to the disassembly of the β-catenin destruction complex, which prevents GSK3β-mediated β-catenin phosphorylation. Thus, β-catenin can translocate to the nucleus where it binds to the TCF/Lef, initiating the transcription of Wnt-related genes. When inactivated, the β-catenin destruction complex remains stabilized, allowing the phosphorylation of β-catenin, inducing its degradation by the proteasome. However, the non-canonical Wnt/PCP pathway requires non-canonical Wnt ligands, which will interact with the Fz receptor and will activate Dvl. However, at this point, Dvl induces the activation of RhoA and Rac, which ultimately will lead to cytoskeletal rearrangement. Similarly, a secondary non-canonical Wnt pathway, known as Wnt/Ca²⁺, can be triggered by non-canonical Wnt ligands. In this case, Fz will induce the release of calcium from intracellular stores, leading to the activation of calcineurin, CamKII, and PKC. Fz, frizzled receptor; LRP, low-density lipoprotein receptor-related protein; Dvl, disheveled; APC, adenomatous polyposis coli; GSK3β, glycogen synthase kinase 3 β; TCF/Lef, T-cell factor/lymphoid enhancer factor; PCP, planar cell polarity; RhoA, Ras homolog gene family member A; ROCK, rho-associated protein kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; JNK, c-Jun N-terminal kinase; PKC, protein kinase C; CamKII, calcium/calmodulin kinase II.

Figure 3

Proposed molecular talking points between TLRs, Wnt, and nuclear factor-κB (NF-κB). The schematic summarizes the suggested interplaying molecular nodes between the different signaling pathways addressed in the present review. (A) According to the literature, TLRs can modulate the activity of Wnt signaling at different points. TLRs can prevent the activation of LRP6, supporting the function of the β-catenin destruction complex, thereby promoting the degradation of β-catenin and blocking the expression of Wnt target genes. In contrast, TLRs can lead, through PI3K and IKKε, to the activation of Akt, causing the inhibition of GSK3β. However, TLR signaling can also lead to NLK activation, which can interact with the Lef member of the TCF/Lef transcription factor. (B) Similarly, Wnt signaling, through its different pathways, can modulate the activity of the TLRs. The non-canonical Wnt/Ca²⁺ pathway can induce, through TAK1, the activation of SOC1 and PIAS1, causing a reduced expression of TLR signal transducers, such as Myd88. Similarly, the non-canonical Wnt/PCP can interact through Rac1/PI3K/Akt with the IKK complex, modulating the activation of NF-κB. In the case of canonical Wnt signaling, direct modulation of the NF-κB through a Wnt-mediated RelA interaction has been demonstrated. Moreover, it has been suggested that β-catenin can block the interaction between NF-κB and CBP/P300, preventing the transcription of NF-κB-target genes. TLR, toll-like receptor; MyD88, myeloid differentiation factor 88; TAK1, transforming growth factor-β-activated kinase-1; IKK, inhibitory NF-κB kinase; NLK, nemo-like kinase; PI3K, phosphatidylinositide-3 kinase; Akt, protein kinase B; LRP6, low-density lipoprotein receptor-related protein 6; GSK3β, glycogen synthase kinase 3 β; TCF/Lef, T-cell factor/lymphoid enhancer factor; PCP, planar cell polarity; Rac1, Ras-related C3 botulinum toxin substrate 1; SOC1, suppressor of cytokine signaling 1; PIAS1, protein inhibitors of activated STAT 1; CBP, CREB-binding protein, RelA, p65 subunit.