Proinflammatory cytokines provoke oxidative damage to actin in neuronal cells mediated by Rac1 and NADPH oxidase.
The proinflammatory cytokines TNFalpha and Il-1beta orchestrate the progression of CNS inflammation, which substantially contributes to neurodegeneration in many CNS pathologies. TNFalpha and Il-1beta stimulate actin filament reorganization in non-neuronal cells often accompanied by the formation of reactive oxygen species (ROS). Actin filament dynamics is vital for cellular plasticity, mitochondrial function, and gene expression despite being highly susceptible to oxidative damage. We demonstrated that, in neuronal cells, TNFalpha and Il-1beta stimulate a transient, redox-dependent reorganization of the actin cytoskeleton into lamellipodia under the regulation of Rac1 and a neuronal NADPH oxidase as the source of ROS. The persistent presence of intracellular ROS provoked oxidative damage (carbonylation) to actin coinciding with the loss of lamellipodia and arrest of cellular plasticity. Inhibition of NADPH oxidase activity or Rac1 abolished the adverse effects of cytokines. These findings suggest that oxidative damage to the neuronal actin cytoskeleton could represent a key step in CNS neurodegeneration.
Department of Chemistry and Biochemistry, University of Alaska Fairbanks, 900 Yukon Drive, REIC 194, Fairbanks, AK 99775, USA.
Brian M
BM
Barth
Shelli
S
Stewart-Smeets
Thomas B
TB
Kuhn
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D000199:Actins; D016207:Cytokines; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein