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Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system

Abstract

Multiple sclerosis is a neuroinflammatory disease associated with axonal degeneration1,2. The neuronally expressed, proton-gated acid-sensing ion channel-1 (ASIC1)3,4 is permeable to Na+ and Ca2+, and excessive accumulation of these ions is associated with axonal degeneration5. We tested the hypothesis that ASIC1 contributes to axonal degeneration in inflammatory lesions of the central nervous system (CNS). After induction of experimental autoimmune encephalomyelitis (EAE), Asic1−/− mice showed both a markedly reduced clinical deficit and reduced axonal degeneration compared to wild-type mice. Consistently with acidosis-mediated injury, pH measurements in the spinal cord of EAE mice showed tissue acidosis sufficient to open ASIC1. The acidosis-related protective effect of Asic1 disruption was also observed in nerve explants in vitro. Amiloride, a licensed and clinically safe blocker of ASICs, was equally neuroprotective in nerve explants and in EAE. Although ASICs are also expressed by immune cells, this expression is unlikely to explain the neuroprotective effect of Asic1 inactivation, as CNS inflammation was similar in wild-type and Asic1−/− mice. In addition, adoptive transfer of T cells from wild-type mice did not affect the protection mediated by Asic1 disruption. These results suggest that ASIC1 blockers could provide neuroprotection in multiple sclerosis.

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Figure 1: Asic1 disruption ameliorates disease severity in EAE mice.
Figure 2: Acidosis in inflammatory CNS tissue and upregulation of ASIC1 in inflammatory EAE brains mediate axonal degeneration.
Figure 3: ASIC1 disruption or blockade by amiloride ameliorates disease severity and axonal loss in EAE mice.
Figure 4: The neuroprotective effect of ASIC1 inactivation or blockade does not depend on ASIC1-expressing T cells.

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Acknowledgements

We thank C. Pugh's laboratory for assistance with HIF-1α western blotting. Work in the authors' laboratories is supported by the Danish (L.F.) and UK Medical Research Councils (L.F., A.V.), the Karen Elise Jensen Foundation, the Lundbeck Foundation, the Danish Multiple Sclerosis Society, the European Union (European Commission Descartes Prize and FP6 Neuropromise, Functional Genomics in Mutant Mouse Models as Tools to Investigate the Complexity of Human Immunological Disease (Mugen) and Autoimmunity and Rheumatic Disease Research Groups (ARDIS)) and G.B. Holding (Viby) ApS (L.F.). M.A.F. is supported by the Deutsche Forschungsgemeinschaft (DFG FR1720/1-1) and the Medical Research Council Career Development Fellowship. R.E. is supported by the Schweizerische Multiple Sklerose Gesellschaft and a Berrow Scholarship.

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M.A.F. and L.F. formulated the hypothesis and initiated and organized the study. M.A.F. and M.J.C. performed the main experimental work and analyzed the data. R.E. and S.V. helped with some experimental procedures. L.F. oversaw the experiments, analyzed the data and provided the main funding for the research. A.V. contributed to data discussion. M.A.F. and M.J.C. drafted the manuscript and L.F. and A.V. helped with writing the final manuscript. J.A.W. and M.J.W. generated Asic1−/− mice and the antibody to ASIC1 and contributed to data discussion.

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Correspondence to Lars Fugger.

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Competing interests

The Medical Research Council UK has filed a patent application entitled "Treatment for demyelinating disease" (priority US filing no. 60/830681, priority GB filing no. 0614058.6; priority date 14th July 2006), which is based on the research described in this paper. M.A.F. and L.F. are listed as inventors in this application.

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Supplementary Figures 1 & 2, Supplementary Tables 1–4 and Supplementary Methods (PDF 2977 kb)

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Friese, M., Craner, M., Etzensperger, R. et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat Med 13, 1483–1489 (2007). https://doi.org/10.1038/nm1668

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