Fig. 6.

Model for Wnt5a as a tolerance-associated molecular pattern (TAMP). The proposed model for the homeostatic Wnt5a (TAMP)-TLR4 feedback inhibition in human myeloid cells (red arrows) or DAMP signal in mouse (yellow arrow). 1 A danger signal [e.g., endotoxin (PAMP) or endogenous DAMP] binds TLR4 during infection or cell damage. 2 The TLR4-induced signal leads to an increased expression of Wnt5a. 3 Wnt5a is produced and released, and binds TLR2 and TLR4. 4 The Wnt5a/TLR-induced signal promotes TLR-MyD88-NFκB p50-homodimer formation and induction of the immunosuppressive cytokine IL-10 (dominant in human) and TLR-MyD88-MAPK-AP-1 (dominant in mouse) inducing TNFα in mouse. 5 IL-10 promotes the inhibition of TNFα and induction of the anti-inflammatory Mo-MDSC/M2 phenotype in human