TLR2-Dependent Activation of β-Catenin Pathway in Dendritic Cells Induces Regulatory Responses and Attenuates Autoimmune Inflammation

Abstract

Dendritic cells (DCs) sense microbes via multiple innate receptors. Signals from different innate receptors are coordinated and integrated by DCs to generate specific innate and adaptive immune responses against pathogens. Previously, we have shown that two pathogen recognition receptors, TLR2 and dectin-1 that recognize the same microbial stimulus (zymosan) on DCs, induce mutually antagonistic regulatory or inflammatory responses, respectively. How diametric signals from these two receptors are coordinated in DCs to regulate or incite immunity is not known. Here we show that TLR2-signaling via AKT activates the β-catenin/TCF4 pathway in DCs and programs them to drive T regulatory cell differentiation. Activation of β-catenin/TCF4 was critical to induce regulatory molecules interleukin-10 (Il-10) and vitamin A metabolizing enzyme retinaldehyde dehydrogenase 2 (Aldh1a2) and to suppress pro-inflammatory cytokines. Deletion of β-catenin in DCs programmed them to drive TH17/TH1 cell differentiation in response to zymosan. Consistent with these findings, activation of the β-catenin pathway in DCs suppressed chronic inflammation and protected mice from TH17/TH1-mediated autoimmune neuroinflammation. Thus activation of β-catenin in DCs via the TLR2 receptor is a novel mechanism in DCs that regulates autoimmune inflammation.

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

“…In the present studies, we postulated that TLR tolerance could explain the TLR2 paradox in EAE as well as offer a potential mechanism for microbiome-mediated immune regulation. Our study differs from the polysaccharide A and zymosan studies (11)(12)(13)(14) in that we show TLR tolerance induction using a very low dose of a canonical TLR2 ligand and the microbiomederived TLR ligand known to access human serum, L654, attenuate EAE. Additionally, our study differs in our sole use of adoptive transfer EAE and in the effector and regulatory alterations we found associated with TLR tolerance-induced disease attenuation.…”

“…The TLR2 ligands, polysaccharide A and zymosan, when administered to mice during EAE (in the range of ∼100 mg per day), significantly reduced disease severity via induction of various subsets of Tregs (11)(12)(13)(14). In the present studies, we postulated that TLR tolerance could explain the TLR2 paradox in EAE as well as offer a potential mechanism for microbiome-mediated immune regulation.…”

“…Previous reports in which TLR2 ligands were administered or TLR2 was genetically deleted in mice with EAE showed an increase in CD39-expressing, CD62L-expressing, or IL-10-producing Tregs (8,13,14). It should be noted that in these studies significantly larger concentrations of TLR2 ligands were administered (100 mg) than were used in our tolerance studies (0.35 mg Pam2Cys and 5 mg L654).…”

“…In contrast to the potential requirement for TLR2 in the EAE disease process, other studies have reported that administering relatively large amounts of TLR2 ligands can attenuate EAE through induction of various Treg populations (11)(12)(13)(14). Thus, although the literature appears contradictory in suggesting both a requirement for and inhibitory capacity of TLR2 signaling in EAE, the concept of TLR tolerance can potentially resolve this paradox.…”

Eixo IL-4/STAT-6/SOCS-5 na diferenciação das células dendríticas: efeitos da melatonina.

“…Todavia, não se pode ignorar que as DCs têm, também, outro papel essencial na manutenção do equilíbrio imune no organismo -a indução e manutenção da tolerância imunológica (CASTELLANO et al, 2004;MANOHARAN et al, 2014;NUSSEZWEIG, 2002;STEINMAN, 2003). Embora chamadas de "imaturas" quando não ativadas pelo desequilíbrio homeostático no tecido, as DCs, neste estado, são muito importantes para apresentar ao sistema imune antígenos presentes nos tecidos sadios, de maneira a evitar que se desencadeiem respostas destrutivas contra os mesmos (IDOYAGA et al, 2013;NUSSENZWEIG, 2002;STEINMAN, 2003), mantendo, portanto, a homeostasia tecidual.…”