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

The Journal of Immunology : Official Journal of the American Association of Immunologists
Jennifer K DowlingAshley Mansell

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...Continue Reading

References

Mar 1, 1994·The Journal of General Virology·E M AndersR A Ezekowitz
Aug 30, 2001·Nature Immunology·T HorngR Medzhitov
Dec 6, 2001·Nature Reviews. Genetics·G S Cooke, A V Hill
Jan 24, 2002·Current Opinion in Critical Care·R C Read, D H Wyllie
Feb 28, 2002·Annual Review of Immunology·Jean-Laurent Casanova, Laurent Abel
Sep 6, 2002·Biochemical Pharmacology·Linda VermeulenGuy Haegeman
Dec 20, 2002·Nature·Jonathan Cohen
Jun 24, 2003·American Journal of Physiology. Lung Cellular and Molecular Physiology·Evan S OngAsrar B Malik
Dec 20, 2003·Nature·UNKNOWN International HapMap Consortium
Sep 17, 2005·Science·Markus W CovertDavid Baltimore
Nov 23, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Samithamby JeyaseelanG Scott Worthen
Jun 27, 2006·Paediatric Respiratory Reviews·James G MartinMuhannad Hassan
Dec 8, 2007·The Lancet Infectious Diseases·Tom van der Poll, Steven M Opal
Feb 29, 2008·Nature Genetics·Sergey NejentsevRolf D Horstmann
Apr 18, 2008·Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases·John CastiblancoJuan-Manuel Anaya
Mar 7, 2009·Cytokine·Kristie A Jenkins, Ashley Mansell
Jun 11, 2009·The Journal of Biological Chemistry·Kamalpreet NagpalDouglas T Golenbock
Sep 1, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Elaine F KennyLuke A J O'Neill
Nov 6, 2009·Journal of Leukocyte Biology·Leah E ColeStefanie N Vogel
Feb 19, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Julie GeorgeAlexander N R Weber
Mar 23, 2010·Cell·Osamu Takeuchi, Shizuo Akira
Jun 8, 2010·Critical Care : the Official Journal of the Critical Care Forum·Oliver KumpfRalf R Schumann
Aug 30, 2011·Proceedings of the National Academy of Sciences of the United States of America·Eugene ValkovBostjan Kobe
Dec 22, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ty Dale TroutmanChandrashekhar Pasare
May 23, 2012·Nature Immunology·Mihai G NeteaLuke A J O'Neill
Jun 6, 2012·Current Drug Targets·Thomas VeStuart Kellie
May 3, 2013·Nature·Kari Ann ShireyStefanie N Vogel
Jun 19, 2013·Virulence·Willem Joost WiersingaTom van der Poll
Aug 29, 2013·IUBMB Life·Nicholas J Bernard, Luke A O'Neill
Jan 28, 2016·Mucosal Immunology·K A ShireyS N Vogel
Feb 18, 2016·Immunity·Clíona Ní CheallaighJoseph Keane
Mar 3, 2017·Molecular Immunology·Parimala R VajjhalaBostjan Kobe
Jul 26, 2017·Proceedings of the National Academy of Sciences of the United States of America·Mark M HughesLuke A J O'Neill
Aug 2, 2017·Nature Structural & Molecular Biology·Thomas VeBostjan Kobe
Jan 13, 2018·Methods in Molecular Biology·Ashley Mansell, Michelle D Tate

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