Aung, T.; Song, S.; Kasongo, J.; Harada, H.; Zhang, S.; Henegariu, O.; Chae, W.-J.

Dickkopf1(DKK1) is a quintessential Wnt antagonist and immunomodulator in various inflammatory diseases. The underlying molecular mechanisms of DKK1-mediated immunomodulation remain elusive. Here, we identified TLR4 as a new receptor for DKK1 to activate NF{kappa}B pathway-mediated gene expressions and pyroptosis via NLRP3 inflammasome in human and mouse macrophages. DKK1 employed TLR4 to initiate NF{kappa}B signaling cascade via MyD88. MyD88-TAK1-NF{kappa}B pathway activation by DKK1 increased HIF1, NF{kappa}B, and NLRP3 protein expression levels, leading to pyroptosis. Unlike LPS, DKK1 did not induce IRAK4 phosphorylation, while the interaction between MyD88 and IRAK4 was maintained for downstream signaling activation. DKK1 did not induce IRF3 phosphorylation in the nucleus and failed to induce IFN{beta} gene expression, indicating differential signaling from LPS. DKK1 primed macrophages via TLR4-MyD88, resulting in NLRP3 inflammasome-mediated pyroptosis via Caspase-1 and Gasdermin D maturation with various NLRP3 inflammasome activators, including Nigericin. Our results demonstrated that DKK1 is a novel endogenous priming ligand that augments differential NF{kappa}B pathway from LPS and NLRP3 inflammasome activation via TLR4 in mouse and human macrophages.