Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation

Journal of Neuroinflammation
Suzanne A B M AartsEsther Lutgens

Abstract

The influx of leukocytes into the central nervous system (CNS) is a key hallmark of the chronic neuro-inflammatory disease multiple sclerosis (MS). Strategies that aim to inhibit leukocyte migration across the blood-brain barrier (BBB) are therefore regarded as promising therapeutic approaches to combat MS. As the CD40L-CD40 dyad signals via TNF receptor-associated factor 6 (TRAF6) in myeloid cells to induce inflammation and leukocyte trafficking, we explored the hypothesis that specific inhibition of CD40-TRAF6 interactions can ameliorate neuro-inflammation. Human monocytes were treated with a small molecule inhibitor (SMI) of CD40-TRAF6 interactions (6877002), and migration capacity across human brain endothelial cells was measured. To test the therapeutic potential of the CD40-TRAF6-blocking SMI under neuro-inflammatory conditions in vivo, Lewis rats and C57BL/6J mice were subjected to acute experimental autoimmune encephalomyelitis (EAE) and treated with SMI 6877002 for 6 days (rats) or 3 weeks (mice). We here show that a SMI of CD40-TRAF6 interactions (6877002) strongly and dose-dependently reduces trans-endothelial migration of human monocytes. Moreover, upon SMI treatment, monocytes displayed a decreased production of RO...Continue Reading

References

Nov 1, 1993·European Journal of Biochemistry·L M Henderson, J B Chappell
Mar 19, 1996·Proceedings of the National Academy of Sciences of the United States of America·K GerritseE Claassen
Jan 29, 1999·Research in Immunology·T OwensM Krakowski
Oct 18, 2000·The Cochrane Database of Systematic Reviews·G FilippiniL Candelise
Jun 26, 2001·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·J JensenF Sellebjerg
Aug 2, 2001·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·A Van der GoesH E De Vries
Mar 5, 2002·Nature Medicine·Patrick AndréDenisa D Wagner
Apr 17, 2002·Lancet·Alastair Compston, Alasdair Coles
Sep 5, 2002·European Journal of Immunology·Jon D LamanJan Ceuppens
Mar 12, 2003·Biochemical Pharmacology·Jerome J A HendriksChristine D Dijkstra
Nov 12, 2003·The Journal of Allergy and Clinical Immunology·Tanuja Chitnis, Samia J Khoury
Dec 22, 2004·The Journal of Experimental Medicine·Jerome J A HendriksHelga E de Vries
Mar 19, 2005·Science·Jennifer Couzin
Sep 6, 2005·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·B B WekslerP O Couraud
Apr 14, 2006·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·C P LarsenA D Kirk
Jan 16, 2007·Annual Review of Medicine·Philip L De Jager, David A Hafler
Jul 15, 2009·Seminars in Immunology·Anna L PetersGail A Bishop
Jul 21, 2009·Seminars in Immunology·David EngelEsther Lutgens
Jul 29, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Ranjana AdvaniJonathan G Drachman
Jul 6, 2010·Biochimica Et Biophysica Acta·Jack van HorssenHelga E de Vries
Jul 16, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Servio H RamirezYuri Persidsky
Jun 21, 2012·Nature Reviews. Neuroscience·Peter K StysJeroen J G Geurts
Jun 26, 2012·Immunological Reviews·Lior MayoHoward L Weiner
Mar 5, 2013·Journal of Neuroinflammation·Daphne Y S VogelChristine D Dijkstra
Aug 29, 2013·Advanced Drug Delivery Reviews·Jörg Kreuter
Dec 7, 2013·Nature Medicine·Birgit ObermeierRichard M Ransohoff
Feb 5, 2014·Proceedings of the National Academy of Sciences of the United States of America·Antonios ChatzigeorgiouEsther Lutgens
Nov 29, 2014·Archives of Medical Research·Genaro Gabriel OrtizMoisés Alejandro Alatorre-Jiménez
Jan 28, 2015·Journal of Chemical Information and Modeling·Barbara ZarzyckaGerry A F Nicolaes
Mar 11, 2015·European Journal of Immunology·Daphne Y S VogelChristine D Dijkstra

❮ Previous
Next ❯

Citations

Jan 10, 2018·Frontiers in Immunology·Suzanne A B M AartsEsther Lutgens
Jun 23, 2018·Arteriosclerosis, Thrombosis, and Vascular Biology·Ellen Rouwet, Esther Lutgens
Nov 25, 2018·The Journal of Pathology·Suzanne Abm AartsEsther Lutgens
May 24, 2019·European Heart Journal·Esther LutgensChristian Weber
Mar 13, 2018·Current Pharmacology Reports·Almin I LalaniPing Xie
Jan 9, 2018·Cardiovascular Research·Pascal J H KustersTom T P Seijkens
Dec 10, 2020·BioMed Research International·Jingjing WangGuixiang Tai
Nov 28, 2017·Translational Research : the Journal of Laboratory and Clinical Medicine·Muhammad AbdullahMonte S Willis
Jul 3, 2021·Biomedicines·Ilenia SavinettiMaria Foti

❮ Previous
Next ❯

Methods Mentioned

BETA
FCS
FACS
flow cytometry
enzyme-linked immunosorbent assay
PCR
flow
ELISA

Software Mentioned

FlowJo
GraphPad Prism
GraphPad

Related Concepts

Related Feeds

Blood Brain Barrier Chips

The blood brain barrier (BBB) is comprised of endothelial cells that regulate the influx and outflux of plasma concentrations. Lab-on-a-chip devices allow scientists to model diseases and mechanisms such as the passage of therapeutic antibodies across the BBB. Discover the latest research on BBB chips here.

Blood Brain Barrier & Cytokines

Some cytokines are able to cross the blood brain barrier through transport systems and enter the cerebrospinal fluid and interstitial fluid spaces. Here is the latest research on cytokines crossing the blood brain barrier and how this can affect tissues within the CNS.

Blood Brain Barrier Regulation in Health & Disease

The blood brain barrier is essential in regulating the movement of molecules and substances in and out of the brain. Disruption to the blood brain barrier and changes in permeability allow pathogens and inflammatory molecules to cross the barrier and may play a part in the pathogenesis of neurodegenerative disorders. Here is the latest research in this field.

Blood Brain Barrier

The blood brain barrier is a border that separates blood from cerebrospinal fluid. Discover the latest search on this highly selective semipermeable membrane here.

Anti-inflammatory Treatments

A drug or substance that reduces inflammation (redness, swelling, and pain) in the body. Anti-inflammatory agents block certain substances in the body that cause inflammation and swelling. Discover the latest research on anti-inflammatory treatments here

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.

Related Papers

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Aaron P KithcartCaroline C Whitacre
The Journal of Immunology : Official Journal of the American Association of Immunologists
Gerty SchreibeltHelga E de Vries
© 2022 Meta ULC. All rights reserved