Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation

Agata A Mossakowski, Julian Pohlan, Daniel Bremer, Randall Lindquist, Jason M Millward, Markus Bock, Karolin Pollok, Ronja Mothes, Leonard Viohl, Moritz Radbruch, Jenny Gerhard, Judith Bellmann-Strobl, Janina Behrens, Carmen Infante-Duarte, Anja Mähler, Michael Boschmann, Jan Leo Rinnenthal, Martina Füchtemeier, Josephine Herz, Florence C PacheMarkus Bardua, Josef Priller, Anja E Hauser, Friedemann Paul, Raluca Niesner, Helena Radbruch

Research output: Contribution to journalArticlepeer-review

Abstract

The functional dynamics and cellular sources of oxidative stress are central to understanding MS pathogenesis but remain elusive, due to the lack of appropriate detection methods. Here we employ NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX enzymes) in vivo to identify inflammatory monocytes, activated microglia, and astrocytes expressing NOX1 as major cellular sources of oxidative stress in the central nervous system of mice affected by experimental autoimmune encephalomyelitis (EAE). This directly affects neuronal function in vivo, indicated by sustained elevated neuronal calcium. The systemic involvement of oxidative stress is mirrored by overactivation of NOX enzymes in peripheral CD11b(+) cells in later phases of both MS and EAE. This effect is antagonized by systemic intake of the NOX inhibitor and anti-oxidant epigallocatechin-3-gallate. Together, this persistent hyper-activation of oxidative enzymes suggests an "oxidative stress memory" both in the periphery and CNS compartments, in chronic neuroinflammation.

Original languageEnglish
Pages (from-to)799-814
Number of pages16
JournalActa Neuropathologica
Volume130
Issue number6
Early online date31 Oct 2015
DOIs
Publication statusE-pub ahead of print - 31 Oct 2015

Keywords

  • Animals
  • Antioxidants
  • Astrocytes
  • CD11b Antigen
  • Calcium
  • Catechin
  • Chronic Disease
  • Disease Progression
  • Encephalomyelitis, Autoimmune, Experimental
  • Enzyme Inhibitors
  • Glatiramer Acetate
  • Humans
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Multiple Sclerosis
  • NADPH Oxidases
  • Neurons
  • Oxidative Stress
  • Journal Article
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

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