Blocking PDGFR-a decreases multiple sclerosis-like neuroinflammation by inhibiting disruption of blood brain barrier integrity
ECTRIMS Online Library. Zeitelhofer M. 09/13/19; 278693; P1654
Manuel Zeitelhofer
Manuel Zeitelhofer
Contributions
Abstract

Abstract: P1654

Type: Poster Sessions

Abstract Category: Poster Session 3

M. Zeitelhofer1, M.Z. Adzemovic1,2, J. Huang2, C. Stefanitsch1, C. Mössinger1, S. Hochmeister3, C. Strell4, L. Muhl1, H. Lassmann5, I. Kockum2, L. Fredriksson1, T. Olsson2, I. Nilsson1, U. Eriksson1

1MBB, Karolinkska Institute, 2Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden, 3Medical University of Graz, Graz, Austria, 4Stockholm University, Stockholm, Sweden, 5Medical University Vienna, Vienna, Austria

Disruption of blood-brain barrier (BBB) integrity is a hallmark of several neurological disorders. Here we show that the BBB is dynamically and differentially affected during the preclinical, progression and remission phases of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Interplay of pro-inflammatory and pro-angiogenic mediators identified in the BBB transcriptome and down-regulation of endothelial tight junction components coincided with increased BBB leakage specifically during the progression phase distinctively counteracted by blocking PDGFRα. Specific targeting of the PDGFRα ligand utilizing a neutralizing antibody recapitulated restoration of BBB integrity and amelioration of EAE symptoms. Intracerebroventricular injection of the PDGFRα ligand induced upregulation whereas blocking the PDGFRα ligand during EAE revealed downregulation of Tnf and Il1a at the BBB. Taken together, these findings suggest that blocking the PDGFRα ligand counteracts fundamental aspects of endothelial cell activation and barrier loss in part by decreasing Tnf and Il1a expression at the BBB, leading to improved BBB integrity.
Disclosure: This work was supported by the Swedish Research Council (2016-02593, 2017-000691, 2017-01794), the Swedish Cancer Foundation (CAN 16/633) and the Hållsten Research Foundation (to U. Eriksson), the Swedish Heart and Lung foundation (to I. Nilsson), Karolinska Institutet (to I. Nilsson and M. Zeitelhofer), Neurofonden (to M.Z. Adzemovic and M. Zeitelhofer), Tore Nilsons Stiftelse (to M.Z. Adzemovic) and the Wallenberg foundation (to T. Olsson)

Abstract: P1654

Type: Poster Sessions

Abstract Category: Poster Session 3

M. Zeitelhofer1, M.Z. Adzemovic1,2, J. Huang2, C. Stefanitsch1, C. Mössinger1, S. Hochmeister3, C. Strell4, L. Muhl1, H. Lassmann5, I. Kockum2, L. Fredriksson1, T. Olsson2, I. Nilsson1, U. Eriksson1

1MBB, Karolinkska Institute, 2Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden, 3Medical University of Graz, Graz, Austria, 4Stockholm University, Stockholm, Sweden, 5Medical University Vienna, Vienna, Austria

Disruption of blood-brain barrier (BBB) integrity is a hallmark of several neurological disorders. Here we show that the BBB is dynamically and differentially affected during the preclinical, progression and remission phases of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Interplay of pro-inflammatory and pro-angiogenic mediators identified in the BBB transcriptome and down-regulation of endothelial tight junction components coincided with increased BBB leakage specifically during the progression phase distinctively counteracted by blocking PDGFRα. Specific targeting of the PDGFRα ligand utilizing a neutralizing antibody recapitulated restoration of BBB integrity and amelioration of EAE symptoms. Intracerebroventricular injection of the PDGFRα ligand induced upregulation whereas blocking the PDGFRα ligand during EAE revealed downregulation of Tnf and Il1a at the BBB. Taken together, these findings suggest that blocking the PDGFRα ligand counteracts fundamental aspects of endothelial cell activation and barrier loss in part by decreasing Tnf and Il1a expression at the BBB, leading to improved BBB integrity.
Disclosure: This work was supported by the Swedish Research Council (2016-02593, 2017-000691, 2017-01794), the Swedish Cancer Foundation (CAN 16/633) and the Hållsten Research Foundation (to U. Eriksson), the Swedish Heart and Lung foundation (to I. Nilsson), Karolinska Institutet (to I. Nilsson and M. Zeitelhofer), Neurofonden (to M.Z. Adzemovic and M. Zeitelhofer), Tore Nilsons Stiftelse (to M.Z. Adzemovic) and the Wallenberg foundation (to T. Olsson)

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