Final Report Summary - NEUROINFLAMMATION (nEUROinflammation)
In Europe about 650,000 patients die from strokes each year and a similar number suffers from multiple sclerosis. Both disorders have a marked neuroinflammatory response in common, while the relative importance of the innate and adaptive immunity seems to differ. The two arms of the immune system are linked by myeloid cells, i.e. resident microglia and invading bone marrow-derived macrophages. Intriguingly, myeloid cells exert both detrimental and beneficial effects in the brain, while the underlying mechanisms are largely unclear. The Marie Curie Initial Training Network (ITN) nEUROinflammation funded by the European Commission Seventh Framework Programme (FP7) for Research and Technological Development has searched for strategies to modulate myeloid cell behaviour in the brain for therapeutic purposes. This study included the blood-brain barrier as the gate-keeper that controls the invasion of myeloid cells. A unique feature of this ITN has been the combination of stroke and multiple sclerosis research in order to release synergies between the fields and to provide a comprehensive picture of neuroinflammation. This ITN has aimed at one goal: to modulate basic neuroinflammatory mechanisms for the treatment of neurological diseases.
In nEUROinflammation sixteen partners from the academic and private sector with complementary scientific background have joined forces. Partners have expertise in various models of stroke and multiple sclerosis. Furthermore, they have acquired a large toolbox of methods to characterize neuroinflammation in an experimental and clinical setting. By employing a range of experimental and translational techniques partners have trained 16 Early Stage Researcher (ESRs) in neuroinflammatory concepts and technologies that are valid across specific disease entities. Work was structured according to key cellular players of neuroinflammation, i.e. bone marrow-derived macrophages (WP1), endothelial cells (WP2), and resident microglia (WP3). In four very fruitful scientific meetings in Caen, Brescia (both in 2014), Warsaw (2016), and Lübeck (2017), as well as a summer school in Lübeck 2015 we have reinforced our close collaborations and coordinated our efforts to approach the research questions.
Starting on October 1st 2013, nEUROinflammation ran for four years until 30th September 2017. All milestones and deliverables could be accomplished. In WP1 “Bone-marrow derived macrophages and dendritic cells in neuroinflammation” Marta Jordao (ESR1), Freiburg, Germany, has investigated the transcriptome and the turnover rates of bone marrow-derived macrophages and their role in activating T cells in experimental autoimmune encephalomyelitis. Mattia Gallizioli (ESR2), Barcelona, Spain, has characterized the effect of dendritic cell expansion on stroke outcome. In this context, Rittika Chunder (ESR3), Lübeck, Germany, has analyzed autoantibodies in human stroke patients in close cooperation with partner 2 in Barcelona, Spain. Meike Keuters (ESR4), Kuopio, Finland, has defined the pharmacological properties of a first-in-class neuroprotective and anti-inflammatory compound and has explored the effect of new lymphatic vessels on ischemic brain damage.
In WP2 “Pivotal role of endothelium in mediating neuroinflammation” Pascale Baden and Mariana Mota Castro Dias (ESR5), Bern, Switzerland, have studied the function of claudin 3 for the blood-brain barrier and the development of experimental autoimmune encephalomyelitis using knockout mice. Omar Chuquisana (ESR6), Münster, Germany, has investigating the role of β2 integrin for the adhesion of neutrophils to endothelial cells in ischemic stroke. Focusing on the barrier properties of endothelial cells Claudio Derada Troletti (ESR7), Amsterdam, Netherlands, has investigated the role of miRNAs during inflammation. The work of Anupriya Mehra (ESR8), Caen, France, has centered on the role of NMDA receptors in brain endothelial cells targeting these receptors to ameliorate neuroinflammation. Finally, Yun Jiang (ESR9), Lübeck, Germany, has probed the role of the pro-inflammatory NF-κB signaling pathway for small vessel diseases.
In WP3 “Protective and detrimental role of microglia” Wenson D. R. Karunakaran (ESR10), Warsaw, Poland, has characterized microglial gene expression in in-vitro and in-vivo models of glioma and stroke. He focused on epigenetic regulation of microglial gene expression together with Mariana Mota (ESR11), Brescia, Italy, who has been able to modulate epigenetic control in the context of cerebral ischemia by using pharmacological tools. Nozha Borjini (ESR12), Parma and Bologna, Italy, has performed a time course analysis of potential biomarkers for inflammation and demyelination in models of multiple sclerosis and ischemic brain injury searching for early markers that predict clinical outcome. Finally, Natalia Kolosowska (ESR13), Kuopio, Finland, has explored the role of exosomal miRNA in the neuroprotection exerted by inflammatory stimuli in a mouse model of stroke.
By consistently pursuing these lines of research, nEUROinflammation has been highly successful in two areas. First the consortium has refined current concepts on how myeloid cells invade the brain in two common neurological diseases and how they shape brain injury. While this may not lead to immediate improvements in health care, it provides a rational and sound basis for further drug development. Up to now the scientific merits of the consortium are documented by 32 publications - and counting. Second and equally important, the consortium takes pride in training 16 talented ESRs that will contribute to the European scientific community and to the future investigation of neuroinflammatory diseases.
For further information please visit the nEUROinflammation website: www.neuroinflammation.eu or contact the coordinator Markus Schwaninger, University of Lübeck, Institute of Pharmacology and Toxicology, Ratzeburger Allee 160, 23538 Lübeck, Germany, Tel.: +49-451-3101 7200, E-Mail: markus.schwaninger@pharma.uni-luebeck.de.
In nEUROinflammation sixteen partners from the academic and private sector with complementary scientific background have joined forces. Partners have expertise in various models of stroke and multiple sclerosis. Furthermore, they have acquired a large toolbox of methods to characterize neuroinflammation in an experimental and clinical setting. By employing a range of experimental and translational techniques partners have trained 16 Early Stage Researcher (ESRs) in neuroinflammatory concepts and technologies that are valid across specific disease entities. Work was structured according to key cellular players of neuroinflammation, i.e. bone marrow-derived macrophages (WP1), endothelial cells (WP2), and resident microglia (WP3). In four very fruitful scientific meetings in Caen, Brescia (both in 2014), Warsaw (2016), and Lübeck (2017), as well as a summer school in Lübeck 2015 we have reinforced our close collaborations and coordinated our efforts to approach the research questions.
Starting on October 1st 2013, nEUROinflammation ran for four years until 30th September 2017. All milestones and deliverables could be accomplished. In WP1 “Bone-marrow derived macrophages and dendritic cells in neuroinflammation” Marta Jordao (ESR1), Freiburg, Germany, has investigated the transcriptome and the turnover rates of bone marrow-derived macrophages and their role in activating T cells in experimental autoimmune encephalomyelitis. Mattia Gallizioli (ESR2), Barcelona, Spain, has characterized the effect of dendritic cell expansion on stroke outcome. In this context, Rittika Chunder (ESR3), Lübeck, Germany, has analyzed autoantibodies in human stroke patients in close cooperation with partner 2 in Barcelona, Spain. Meike Keuters (ESR4), Kuopio, Finland, has defined the pharmacological properties of a first-in-class neuroprotective and anti-inflammatory compound and has explored the effect of new lymphatic vessels on ischemic brain damage.
In WP2 “Pivotal role of endothelium in mediating neuroinflammation” Pascale Baden and Mariana Mota Castro Dias (ESR5), Bern, Switzerland, have studied the function of claudin 3 for the blood-brain barrier and the development of experimental autoimmune encephalomyelitis using knockout mice. Omar Chuquisana (ESR6), Münster, Germany, has investigating the role of β2 integrin for the adhesion of neutrophils to endothelial cells in ischemic stroke. Focusing on the barrier properties of endothelial cells Claudio Derada Troletti (ESR7), Amsterdam, Netherlands, has investigated the role of miRNAs during inflammation. The work of Anupriya Mehra (ESR8), Caen, France, has centered on the role of NMDA receptors in brain endothelial cells targeting these receptors to ameliorate neuroinflammation. Finally, Yun Jiang (ESR9), Lübeck, Germany, has probed the role of the pro-inflammatory NF-κB signaling pathway for small vessel diseases.
In WP3 “Protective and detrimental role of microglia” Wenson D. R. Karunakaran (ESR10), Warsaw, Poland, has characterized microglial gene expression in in-vitro and in-vivo models of glioma and stroke. He focused on epigenetic regulation of microglial gene expression together with Mariana Mota (ESR11), Brescia, Italy, who has been able to modulate epigenetic control in the context of cerebral ischemia by using pharmacological tools. Nozha Borjini (ESR12), Parma and Bologna, Italy, has performed a time course analysis of potential biomarkers for inflammation and demyelination in models of multiple sclerosis and ischemic brain injury searching for early markers that predict clinical outcome. Finally, Natalia Kolosowska (ESR13), Kuopio, Finland, has explored the role of exosomal miRNA in the neuroprotection exerted by inflammatory stimuli in a mouse model of stroke.
By consistently pursuing these lines of research, nEUROinflammation has been highly successful in two areas. First the consortium has refined current concepts on how myeloid cells invade the brain in two common neurological diseases and how they shape brain injury. While this may not lead to immediate improvements in health care, it provides a rational and sound basis for further drug development. Up to now the scientific merits of the consortium are documented by 32 publications - and counting. Second and equally important, the consortium takes pride in training 16 talented ESRs that will contribute to the European scientific community and to the future investigation of neuroinflammatory diseases.
For further information please visit the nEUROinflammation website: www.neuroinflammation.eu or contact the coordinator Markus Schwaninger, University of Lübeck, Institute of Pharmacology and Toxicology, Ratzeburger Allee 160, 23538 Lübeck, Germany, Tel.: +49-451-3101 7200, E-Mail: markus.schwaninger@pharma.uni-luebeck.de.