TLR4 induced Wnt3a-Dvl3 restrains the intensity of inflammation and protects against endotoxin-driven organ failure through GSK3β/β-catenin signaling

Abstract

Background-Accumulating evidence suggests a regulatory role of Wnt proteins in innate immune responses. However, the effects of Wnt3a signaling on TLR4-mediated inflammatory responses are controversial and the signaling crosstalk between TLR4 and Wnt3a remains uncertain.Methods-Gainand Loss-of function approaches were utilized to determine the function of Wnt3a signaling in TLR4-mediated inflammatory responses. Cytokine production at protein and mRNA levels and phosphorylation of signaling molecules were measured by ELISA, qRT-PCR, and Western Blot, respectively. Endotoxemia mouse model was employed to assess the effect of Wnt3a on systemic inflammatory cytokine levels and neutrophil infiltration.Results-LPS stimulation leads to an increase of Wnt3a expression and its downstream molecule, Dvl3, in primary monocytes. Inhibition or silence of Wnt3a or Dvl3 significantly increases the production of pro-inflammatory cytokines (IL-12, IL-6, TNFα), robustly reduces βcatenin accumulation, and enhances the phosphorylation of NF-κB P65 and its DNA binding

Glycogen Synthase Kinase 3β Modulates the Inflammatory Response Activated by Bacteria, Viruses, and Parasites

“…The interaction of PAMPs with TLR culminates in the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) through the Toll/IL-1 receptor (TIR)-domain-containing adaptors, myeloid differentiation primary response gene 88 (MyD88)-or TIR-domain-containing adapter-inducing interferonb (TRIF)-dependent pathway, which controls the expression of inflammatory cytokine genes (9). The activated state of GSK3b promotes the activation of NF-kB, leading to a proinflammatory response; in contrast, activation of TLR2, 4, 5, 9 by the MyD88dependent signaling pathway promotes the Akt (PKB)-dependent inactivation of GSK3b that leads to an anti-inflammatory response by inactivating NF-kB and activating the cAMP-response element binding protein (CREB), the activator protein 1 (AP-1), the signaltransducer and activator of transcription 1-3 (STAT1-3), the nuclear factor erythroid 2-related factor 2 (Nrf2), and b-catenin (6,7,(10)(11)(12)(13). During viral infection, activation of GSK3b by TLR3/TRIF signaling pathway controls the tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6)-mitogen-activated protein kinase mitogen activated protein kinase kinase kinase (MAP3K7)-(TAK1) and receptor-interacting serine/threonine-protein 1(RIP1)/NF-kB axis to positively regulate pro-inflammatory cytokine production.…”

MicroRNA-490-3p inhibits inflammatory responses in LPS-induced acute lung injury of neonatal rats by suppressing the IRAK1/TRAF6 pathway

“…Currently, IRAK and TRAF6 are downstream signaling molecules of toll-like receptors (TLR). After LPS infects the body, it first binds to the serum binding protein LPS binding protein (LBP), and transmits to CD14 molecules to produce a LPS-LBP-CD14 complex, which reciprocates TLR4 and its accessory protein myeloid differentiation protein 2, thereby activating IRAK and TRAF6 in succession (35)(36)(37). As an important signaling molecule, IRAK1 exerts a vital part in TLR/IL-1R-mediated innate immune and inflammation response (38).…”

Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets

“…For example, research in this direction has established the new role of Wnt-β catenin signaling pathway as a negative regulator of LPS-induced TLR4 activation and NF-κB mediated generation of pro-inflammatory immune response without any direct interaction between NF-κB and β-catenin [355] . Also, further study has indicated Wnt3A (Wnt family member 3A) or dishevelled 3 (Dvl3) activates during TRL4 stimulation and inhibits the exaggerated production of pro-inflammatory cytokines (TNF-α, IL-6, and IL-12) and neutrophil infiltration via regulating GSK-β-catenin and NF-κB signaling [356] . In addition, S100 alarmins, comprising of S100 calcium-binding protein A8 (S100A8) [also called myeloid related protein-8 (Mrp-8)] and S100 calcium-binding protein A9 (S100A9) [myeloid related protein-14 (Mrp-14)] are endogenous TLR4 ligands and typically form a heterodimer complex called S100A8/A9 (or Calprotectin) upon their release from myeloid cells [357] .…”