Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis — PNAS

Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis
Felix Meissner1, Kaaweh Molawi1, and Arturo Zychlinsky2
+ Author Affiliations

Department of Cellular Microbiology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany
Edited* by Charles A. Dinarello, University of Colorado, Aurora, CO, and approved June 2, 2010 (received for review February 26, 2010)

↵1F.M. and K.M. contributed equally to this work.

Abstract
ALS is a fatal motor neuron disease of adult onset. Neuroinflammation contributes to ALS disease progression; however, the inflammatory trigger remains unclear. We report that ALS–linked mutant superoxide dismutase 1 (SOD1) activates caspase-1 and IL-1β in microglia. Cytoplasmic accumulation of mutant SOD1 was sensed by an ASC containing inflammasome and antagonized by autophagy, limiting caspase-1–mediated inflammation. Notably, mutant SOD1 induced IL-1β correlated with amyloid-like misfolding and was independent of dismutase activity. Deficiency in caspase-1 or IL-1β or treatment with recombinant IL-1 receptor antagonist (IL-1RA) extended the lifespan of G93A-SOD1 transgenic mice and attenuated inflammatory pathology. These findings identify microglial IL-1β as a causative event of neuroinflammation and suggest IL-1 as a potential therapeutic target in ALS.

caspase-1inflammasomeinterleukin 1Lou Gehrig's diseaseneurodegeneration
Footnotes
2To whom correspondence should be addressed. E-mail: zychlinsky@mpiib-berlin.mpg.de. Author contributions: F.M., K.M., and A.Z. designed research; F.M. and K.M. performed research; F.M., K.M., and A.Z. analyzed data; and F.M., K.M., and A.Z. wrote the paper.
The authors declare no conflict of interest.
See Commentary on page 12741.
↵*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1002396107/-/DCSupplemental.

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Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis — PNAS