Wnt5a is a TLR2/4-ligand that induces tolerance in human myeloid cells

Meliha Mehmeti, Caroline Bergenfelz, Eva Källberg, Camilla Rydberg Millrud, Per Björk, Fredrik Ivars, Bengt Johansson-Lindbom, Sven Kjellström, Ingemar André, Karin Leandersson

Research output: Contribution to journalArticlepeer-review

18 Citations (SciVal)

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.

Original languageEnglish
Article number176
JournalCommunications Biology
Volume2
DOIs
Publication statusPublished - 2019

Subject classification (UKÄ)

  • Immunology in the medical area

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