Abstract
Innate immune responses are rapid, dynamic and highly regulated to avoid overt reactions. This regulation is executed by innate immune tolerance mechanisms that remain obscure. Wnt5a is a signalling protein mainly involved in developmental processes and cancer. The effect of Wnt5a on inflammatory myeloid cells is controversial. Here, we combine primary cell cultures, in vitro binding studies, mass spectrometry and Drosophila protein modelling to show that Wnt5a is a direct ligand of toll-like receptor (TLR) 2 and 4. The binding promotes a MyD88-non-canonical nuclear factor of kappa B (NFκB) and AP-1 signalling cascade, with contradictory profiles in mouse (pro-inflammatory) and human (anti-inflammatory) myeloid immune cells. These data reveal that the true nature of Wnt5a in inflammatory cells, is to regulate TLR signals, and in human myeloid cells it acts as an endogenous, tolerance-associated molecular pattern (TAMP), inducing IL-10 and innate immune tolerance.
Highlights
Innate immune responses are rapid, dynamic and highly regulated to avoid overt reactions
We have previously shown that stimulation of primary human monocytes with rWnt5a in combination with typical TLR4 ligands promotes the differentiation of immunosuppressive monocytic—myeloid derived suppressor cells (MoMDSC) or M2 macrophages from primary human monocytes in vitro[13]
In the current study, we explored the link between Wnt5a and toll-like receptor (TLR) in innate immune cell tolerance
Summary
Innate immune responses are rapid, dynamic and highly regulated to avoid overt reactions. The binding promotes a MyD88-non-canonical nuclear factor of kappa B (NFκB) and AP-1 signalling cascade, with contradictory profiles in mouse (pro-inflammatory) and human (anti-inflammatory) myeloid immune cells These data reveal that the true nature of Wnt5a in inflammatory cells, is to regulate TLR signals, and in human myeloid cells it acts as an endogenous, toleranceassociated molecular pattern (TAMP), inducing IL-10 and innate immune tolerance. The immune system is divided into an innate immune response that reacts immediately with specificity towards exogenous and endogenous dangers, and an acquired immune response, that reacts with a delay but with high specificity eventually leading to immunity Both sides of the immune system are tightly regulated by a mechanism called immunological tolerance that is necessary to avoid harmful overt reactions. The role for TLRs in tolerance induction is still unclear[7]
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