The role of NADPH oxidases in Multiple Sclerosis and its animal model, the experimental autoimmune encephalomyelitis

• Applicants: Dr. Kerstin Göbel; Professor Dr. Sven G. Meuth
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 276786445

• Final Report Year: 2020

Final Report Abstract

Accumulating evidence suggest that oxidative stress plays a major role in the pathogenesis of MS, whereas a specific influence of oxidative stress on BBB dysfunction in MS was unclear so far. Here, we identify nicotinamide adenine dinucleotide phosphate (NADPH) oxidase type 4 (NOX4) as a specific and direct modulator of BBB integrity. Deficiency of NOX4 rendered mice more susceptible to experimental autoimmune encephalomyelitis (an animal model of MS) and was accompanied by a remarkable enhancement of BBB disruption and CNS inflammation. Interestingly, neither NOX1 nor NOX2 was involved in these processes. Murine and human in vitro analysis revealed that lack of NOX4 amplifies leukocyte trafficking via chemokine release by endothelial cells. Further, reduced endothelial NOX4 expression was found in CNS tissue of individuals suffering from MS indicating an important role of NOX4 also in humans. Our study demonstrates, for the first time, that NOX4 is an important and direct regulator of BBB integrity. NOX4 activation can decrease BBB damage and cell invasion during neuroinflammation and may offer a novel strategy for the treatment of MS.

Publications

• Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells. Nat Commun. 2016 May 18;7:11626
  Göbel K, Pankratz S, Asaridou CM, Herrmann AM, Bittner S, Merker M, Ruck T, Glumm S, Langhauser F, Kraft P, Krug TF, Breuer J, Herold M, Gross CC, Beckmann D, Korb-Pap A, Schuhmann MK, Kuerten S, Mitroulis I, Ruppert C, Nolte MW, Panousis C, Klotz L, Kehrel B, Korn T, Langer HF, Pap T, Nieswandt B, Wiendl H, Chavakis T, Kleinschnitz C, Meuth SG
  
• Prothrombin and factor X are elevated in multiple sclerosis patients. Ann Neurol. 2016 Dec;80(6):946-951
  Göbel K, Kraft P, Pankratz S, Gross CC, Korsukewitz C, Kwiecien R, Mesters R, Kehrel BE, Wiendl H, Kleinschnitz C, Meuth SG