Format

Send to

Choose Destination
J Immunol. 2019 Apr 15;202(8):2384-2396. doi: 10.4049/jimmunol.1800501. Epub 2019 Feb 20.

The Single Nucleotide Polymorphism Mal-D96N Mice Provide New Insights into Functionality of Mal in TLR Immune Responses.

Author information

1
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
2
Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria 3168, Australia.
3
Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany.
4
Monash Micro Imaging, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
5
Institute for Glycomics, Griffith University, Southport, Queensland 4122, Australia.
6
School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland 4072, Australia; and.
7
Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605.
8
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; ashley.mansell@hudson.org.au.

Abstract

MyD88 adaptor-like (Mal) protein is the most polymorphic of the four key adaptor proteins involved in TLR signaling. TLRs play a critical role in the recognition and immune response to pathogens through activation of the prototypic inflammatory transcription factor NF-κB. The study of single nucleotide polymorphisms in TLRs, adaptors, and signaling mediators has provided key insights into the function of the corresponding genes but also into the susceptibility to infectious diseases in humans. In this study, we have analyzed the immune response of mice carrying the human Mal-D96N genetic variation that has previously been proposed to confer protection against septic shock. We have found that Mal-D96N macrophages display reduced cytokine expression in response to TLR4 and TLR2 ligand challenge. Mal-D96N macrophages also display reduced MAPK activation, NF-κB transactivation, and delayed NF-κB nuclear translocation, presumably via delayed kinetics of Mal interaction with MyD88 following LPS stimulation. Importantly, Mal-D96N genetic variation confers a physiological protective phenotype to in vivo models of LPS-, Escherichia coli-, and influenza A virus-induced hyperinflammatory disease in a gene dosage-dependent manner. Together, these results highlight the critical role Mal plays in regulating optimal TLR-induced inflammatory signaling pathways and suggest the potential therapeutic advantages of targeting the Mal D96 signaling nexus.

PMID:
30787108
DOI:
10.4049/jimmunol.1800501

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center