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

Mehmeti, Meliha LU ; Bergenfelz, Caroline LU ; Källberg, Eva LU ; Millrud, Camilla Rydberg LU ; Björk, Per; Ivars, Fredrik LU ; Johansson-Lindbom, Bengt LU ; Kjellström, Sven LU ; André, Ingemar LU and Leandersson, Karin LU (2019) In Communications Biology 2.
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... (More)

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.

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author
organization
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type
Contribution to journal
publication status
published
subject
in
Communications Biology
volume
2
publisher
Nature Research
external identifiers
  • scopus:85071184154
ISSN
2399-3642
DOI
10.1038/s42003-019-0432-4
language
English
LU publication?
yes
id
2a6a610a-cd0e-481f-80b7-030eb15a6b7e
alternative location
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509336/
date added to LUP
2019-05-22 14:13:22
date last changed
2019-10-20 05:17:50
@article{2a6a610a-cd0e-481f-80b7-030eb15a6b7e,
  abstract     = {<p>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.</p>},
  articleno    = {176},
  author       = {Mehmeti, Meliha and Bergenfelz, Caroline and Källberg, Eva and Millrud, Camilla Rydberg and Björk, Per and Ivars, Fredrik and Johansson-Lindbom, Bengt and Kjellström, Sven and André, Ingemar and Leandersson, Karin},
  issn         = {2399-3642},
  language     = {eng},
  publisher    = {Nature Research},
  series       = {Communications Biology},
  title        = {Wnt5a is a TLR2/4-ligand that induces tolerance in human myeloid cells},
  url          = {http://dx.doi.org/10.1038/s42003-019-0432-4},
  volume       = {2},
  year         = {2019},
}