Wnt5a Skews Dendritic Cell Differentiation to an Unconventional Phenotype with Tolerogenic Features

Abstract

Dendritic cells (DCs) are critical regulators of immune responses that integrate signals from the innate and adaptive immune system and orchestrate T cell responses toward either immunity or tolerance. Growing evidence points to the Wnt signaling pathway as a pivotal piece in the immune balance and focuses on DCs as a direct target for their immunoregulatory role. Our results show that the increase in Wnt5a signaling during the differentiation of human DCs from monocytes alters their phenotype and compromises their subsequent capacity to mature in response to TLR-dependent stimuli. These Wnt5a-DCs produce scant amounts of IL-12p70 and TNF-α but increased levels of IL-10. Consequently, these Wnt5a-DCs have a reduced capacity to induce Th1 responses that promote IL-10 secretion by CD4 T cells. Changes in the transcriptional profile of Wnt5a-DCs correlate with their unconventional phenotype caused presumably by increased IL-6/IL-10 signaling during the process of DC differentiation. The effect of Wnt5a is not a consequence of β-catenin accumulation but is dependent on noncanonical Ca2+/calmodulin-dependent protein kinase II/NF-κB signaling. Our results therefore suggest that under high levels of Wnt5a, typical of the inflammatory state and sepsis, monocytes could differentiate into unconventional DCs with tolerogenic features.

Recombinant Wnt3a and Wnt5a elicit macrophage cytokine production and tolerization to microbial stimulation via Toll‐like receptor 4

“…Of note, no significant reduction of Wnt-induced cytokine mRNA expression and production was observed in macrophages deficient for TLR2 and the TLR coreceptor, RP105 [30] (data not shown). Similar to previous reports, we observed diminished inflammatory cytokine production upon TLR2 stimulation with Pam 3 CSK 4 [24,26] and TLR9 stimulation with CpG oligonucleotides in macrophages that had been preexposed to recombinant Wnt5a and Wnt3a (Fig. 5A and B).…”

“…Recent studies showed that monocytes, macrophages, DCs, and microglia when preexposed to recombinant Wnt3a and Wnt5a displayed phenotypic changes upon subsequent TLR stimulation, including impaired proinflammatory cytokine expression, elevated IL-10 production, and NF-κB p50-homodimers [21,[24][25][26]. Molecular mechanisms underlying the deactivation by recombinant Wnt3a and Wnt5a remained unclear.…”

Alterations of Dendritic Cells in Sepsis: Featured Role in Immunoparalysis

“…Wnt 5a had no effect on LPS-induced DC maturation but impaired the production IL-12p70 and TNF- α while increasing levels of IL-10. Furthermore, Wnt 5a inhibited the T cell proliferation and fail to prime T cell response [95]. So the two types of signal pathway display an opposite effect and sustain the regulation of DCs differentiation by crosstalking to each other.…”

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

“…Exposure to Wnt5a resulted in increased secretion of IL-10 in blood-derived monocytes. 40 DCs exposed to this ligand express more indolamin-2, 3-dioxygenase, a tryptophan-degrading enzyme with immune regulatory properties, and induce more regulatory T cells. 41 Taken together, these data strongly suggest that Wnt/β-catenin as well as noncanonical Wnt ligands have the ability to shape DCs to a tolerogenic status and thus preventing or regulating adaptive T-cell responses.…”