Activation of β-Catenin in Dendritic Cells Regulates Immunity Versus Tolerance in the Intestine

Abstract

Dendritic cells (DCs) play a vital role in initiating robust immunity against pathogens as well as maintaining immunological tolerance to self antigens. However, the intracellular signaling networks that program DCs to become tolerogenic remain unknown. We report here that the Wnt–β-catenin signaling in intestinal dendritic cells regulates the balance between inflammatory versus regulatory responses in the gut. β-catenin in intestinal dendritic cells was required for the expression of anti-inflammatory mediators such as retinoic acid–metabolizing enzymes, interleukin-10, and transforming growth factor–β, and the stimulation of regulatory T cell induction while suppressing inflammatory effector T cells. Furthermore, ablation of β-catenin expression in DCs enhanced inflammatory responses and disease in a mouse model of inflammatory bowel disease. Thus, β-catenin signaling programs DCs to a tolerogenic state, limiting the inflammatory response.

Transcription factor networks in dendritic cell development

“…However, these reports were disputed by another group who demonstrated that the antibody-based depletion of basophils in the previous studies also removed a key DC population, which actually appears to be necessary for initiating Th2 immunity [38]. More recently, a report claiming the importance of beta-catenin signaling in intestinal DCs to gut tolerance was based upon the selective deletion of this molecule in only DCs, a specious claim given there was also complete deletion in a sizeable fraction of macrophages [39]. These ambiguous results are the byproduct of a strict reliance on cell-surface markers to segregate myeloid populations.…”

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

“…There is strong experimental evidence for the contribution of endogenous Wnt proteins to inflammatory cytokine responses and host defense against pathogens in in vivo models [5,11,20] as well as in a variety of cell culture systems [2,6,13,14,36]. In a model of dietinduced metabolic dysfunction, sFRP5 exerted anti-inflammatory functions in vivo, possibly by interfering with Wnt5a-induced proinflammatory cytokine production [11].…”

“…Clinical associations of elevated Wnt expression and pathway activity with infections [2,3,6] and chronic inflammatory diseases [8,9,11] have sparked significant interest in elucidating immune-related functions of Wnt signaling. There is strong experimental evidence for the contribution of endogenous Wnt proteins to inflammatory cytokine responses and host defense against pathogens in in vivo models [5,11,20] as well as in a variety of cell culture systems [2,6,13,14,36]. In a model of dietinduced metabolic dysfunction, sFRP5 exerted anti-inflammatory functions in vivo, possibly by interfering with Wnt5a-induced proinflammatory cytokine production [11].…”

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

“…Helminth-derived secretory products seem to evoke only mild transcriptional programming and maturation of DCs [21,22]. Interestingly, also proinflammatory cytokines such as TNF or IL-6 [23,24] or tissue disruption induce a similar partially mature phenotype and in the latter case has been attributed to a limited DC activation through the Wnt signaling pathway [25,26]. We and others have demonstrated that DCs conditioned by the inflammatory mediator TNF show a particular maturation phenotype characterized by upregulation of MHC II and costimulatory molecules but no production of cytokines [23,25,27].…”