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

Suzanne A.B.M. Aarts, Tom T.P. Seijkens, Pascal J.H. Kusters, Susanne M.A. van der Pol, Barbara Zarzycka, Priscilla D.A.M. Heijnen, Linda Beckers, Myrthe den Toom, Marion J.J. Gijbels, Louis Boon, Christian Weber, Helga E. de Vries, Gerry A.F. Nicolaes, Christine D. Dijkstra, Gijs Kooij, Esther Lutgens

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: 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. Methods: 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). Results: 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 ROS, tumor necrosis factor (TNF), and interleukin (IL)-6, whereas the production of the anti-inflammatory cytokine IL-10 was increased. Disease severity of EAE was reduced upon SMI treatment in rats, but not in mice. However, a significant reduction in monocyte-derived macrophages, but not in T cells, that had infiltrated the CNS was eminent in both models. Conclusions: Together, our results indicate that SMI-mediated inhibition of the CD40-TRAF6 pathway skews human monocytes towards anti-inflammatory cells with reduced trans-endothelial migration capacity, and is able to reduce CNS-infiltrated monocyte-derived macrophages during neuro-inflammation, but minimally ameliorates EAE disease severity. We therefore conclude that SMI-mediated inhibition of the CD40-TRAF6 pathway may represent a beneficial treatment strategy to reduce monocyte recruitment and macrophage activation in the CNS and has the potential to be used as a co-treatment to combat MS.

Original languageEnglish
Article number105
JournalJournal of Neuroinflammation
Volume14
Issue number1
DOIs
Publication statusPublished - 12 May 2017

Cite this

Aarts, S. A. B. M., Seijkens, T. T. P., Kusters, P. J. H., van der Pol, S. M. A., Zarzycka, B., Heijnen, P. D. A. M., ... Lutgens, E. (2017). Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation. Journal of Neuroinflammation, 14(1), [105]. https://doi.org/10.1186/s12974-017-0875-9
Aarts, Suzanne A.B.M. ; Seijkens, Tom T.P. ; Kusters, Pascal J.H. ; van der Pol, Susanne M.A. ; Zarzycka, Barbara ; Heijnen, Priscilla D.A.M. ; Beckers, Linda ; den Toom, Myrthe ; Gijbels, Marion J.J. ; Boon, Louis ; Weber, Christian ; de Vries, Helga E. ; Nicolaes, Gerry A.F. ; Dijkstra, Christine D. ; Kooij, Gijs ; Lutgens, Esther. / Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation. In: Journal of Neuroinflammation. 2017 ; Vol. 14, No. 1.
@article{d54daf8c5e594c29a31902ccea089ad1,
title = "Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation",
abstract = "Background: 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. Methods: 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). Results: 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 ROS, tumor necrosis factor (TNF), and interleukin (IL)-6, whereas the production of the anti-inflammatory cytokine IL-10 was increased. Disease severity of EAE was reduced upon SMI treatment in rats, but not in mice. However, a significant reduction in monocyte-derived macrophages, but not in T cells, that had infiltrated the CNS was eminent in both models. Conclusions: Together, our results indicate that SMI-mediated inhibition of the CD40-TRAF6 pathway skews human monocytes towards anti-inflammatory cells with reduced trans-endothelial migration capacity, and is able to reduce CNS-infiltrated monocyte-derived macrophages during neuro-inflammation, but minimally ameliorates EAE disease severity. We therefore conclude that SMI-mediated inhibition of the CD40-TRAF6 pathway may represent a beneficial treatment strategy to reduce monocyte recruitment and macrophage activation in the CNS and has the potential to be used as a co-treatment to combat MS.",
keywords = "Co-stimulation, EAE, Inflammation, Monocytes, Multiple sclerosis",
author = "Aarts, {Suzanne A.B.M.} and Seijkens, {Tom T.P.} and Kusters, {Pascal J.H.} and {van der Pol}, {Susanne M.A.} and Barbara Zarzycka and Heijnen, {Priscilla D.A.M.} and Linda Beckers and {den Toom}, Myrthe and Gijbels, {Marion J.J.} and Louis Boon and Christian Weber and {de Vries}, {Helga E.} and Nicolaes, {Gerry A.F.} and Dijkstra, {Christine D.} and Gijs Kooij and Esther Lutgens",
year = "2017",
month = "5",
day = "12",
doi = "10.1186/s12974-017-0875-9",
language = "English",
volume = "14",
journal = "Journal of Neuroinflammation",
issn = "1742-2094",
publisher = "BioMed Central",
number = "1",

}

Aarts, SABM, Seijkens, TTP, Kusters, PJH, van der Pol, SMA, Zarzycka, B, Heijnen, PDAM, Beckers, L, den Toom, M, Gijbels, MJJ, Boon, L, Weber, C, de Vries, HE, Nicolaes, GAF, Dijkstra, CD, Kooij, G & Lutgens, E 2017, 'Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation' Journal of Neuroinflammation, vol. 14, no. 1, 105. https://doi.org/10.1186/s12974-017-0875-9

Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation. / Aarts, Suzanne A.B.M.; Seijkens, Tom T.P.; Kusters, Pascal J.H.; van der Pol, Susanne M.A.; Zarzycka, Barbara; Heijnen, Priscilla D.A.M.; Beckers, Linda; den Toom, Myrthe; Gijbels, Marion J.J.; Boon, Louis; Weber, Christian; de Vries, Helga E.; Nicolaes, Gerry A.F.; Dijkstra, Christine D.; Kooij, Gijs; Lutgens, Esther.

In: Journal of Neuroinflammation, Vol. 14, No. 1, 105, 12.05.2017.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation

AU - Aarts, Suzanne A.B.M.

AU - Seijkens, Tom T.P.

AU - Kusters, Pascal J.H.

AU - van der Pol, Susanne M.A.

AU - Zarzycka, Barbara

AU - Heijnen, Priscilla D.A.M.

AU - Beckers, Linda

AU - den Toom, Myrthe

AU - Gijbels, Marion J.J.

AU - Boon, Louis

AU - Weber, Christian

AU - de Vries, Helga E.

AU - Nicolaes, Gerry A.F.

AU - Dijkstra, Christine D.

AU - Kooij, Gijs

AU - Lutgens, Esther

PY - 2017/5/12

Y1 - 2017/5/12

N2 - Background: 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. Methods: 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). Results: 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 ROS, tumor necrosis factor (TNF), and interleukin (IL)-6, whereas the production of the anti-inflammatory cytokine IL-10 was increased. Disease severity of EAE was reduced upon SMI treatment in rats, but not in mice. However, a significant reduction in monocyte-derived macrophages, but not in T cells, that had infiltrated the CNS was eminent in both models. Conclusions: Together, our results indicate that SMI-mediated inhibition of the CD40-TRAF6 pathway skews human monocytes towards anti-inflammatory cells with reduced trans-endothelial migration capacity, and is able to reduce CNS-infiltrated monocyte-derived macrophages during neuro-inflammation, but minimally ameliorates EAE disease severity. We therefore conclude that SMI-mediated inhibition of the CD40-TRAF6 pathway may represent a beneficial treatment strategy to reduce monocyte recruitment and macrophage activation in the CNS and has the potential to be used as a co-treatment to combat MS.

AB - Background: 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. Methods: 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). Results: 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 ROS, tumor necrosis factor (TNF), and interleukin (IL)-6, whereas the production of the anti-inflammatory cytokine IL-10 was increased. Disease severity of EAE was reduced upon SMI treatment in rats, but not in mice. However, a significant reduction in monocyte-derived macrophages, but not in T cells, that had infiltrated the CNS was eminent in both models. Conclusions: Together, our results indicate that SMI-mediated inhibition of the CD40-TRAF6 pathway skews human monocytes towards anti-inflammatory cells with reduced trans-endothelial migration capacity, and is able to reduce CNS-infiltrated monocyte-derived macrophages during neuro-inflammation, but minimally ameliorates EAE disease severity. We therefore conclude that SMI-mediated inhibition of the CD40-TRAF6 pathway may represent a beneficial treatment strategy to reduce monocyte recruitment and macrophage activation in the CNS and has the potential to be used as a co-treatment to combat MS.

KW - Co-stimulation

KW - EAE

KW - Inflammation

KW - Monocytes

KW - Multiple sclerosis

UR - http://www.scopus.com/inward/record.url?scp=85019052772&partnerID=8YFLogxK

U2 - 10.1186/s12974-017-0875-9

DO - 10.1186/s12974-017-0875-9

M3 - Article

VL - 14

JO - Journal of Neuroinflammation

JF - Journal of Neuroinflammation

SN - 1742-2094

IS - 1

M1 - 105

ER -