Abstract
BackgroundThe 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.MethodsHuman 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).ResultsWe 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.ConclusionsTogether, 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.
Highlights
The influx of leukocytes into the central nervous system (CNS) is a key hallmark of the chronic neuro-inflammatory disease multiple sclerosis (MS)
Inhibition of CD40-tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) interactions by small molecule inhibitor (SMI) 6877002 reduces trans-endothelial migration of human monocytes and reactive oxygen species (ROS) production by these cells As migration of inflammatory cells across the blood-brain barrier (BBB) represents a pathological hallmark of MS, we analysed the effects of the CD40-TRAF6-blocking SMI on monocyte migration across an in vitro BBB [31]
Activation of CD40 signalling in monocytes using the agonistic CD40 antibody G28.5 and IFN-γ increased their trans-endothelial migration across non-activated Endothelial cells (ECs) by 210% (1 h vehicle pretreated) or 146% (Fig. 1a)
Summary
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 regarded as promising therapeutic approaches to combat MS. After BBB passage, monocyte-derived macrophages and T cells promote lesion formation and cause axonal damage [1,2,3, 5, 6]. These immune cells secrete pro-inflammatory cytokines and chemokines that promote the recruitment of other immune cells, which amplifies the inflammatory response [1,2,3, 7]. There is a high and unmet need for the development of novel and more specific therapeutic strategies
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