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Molecular Medicine

, Volume 20, Issue 1, pp 350–358 | Cite as

α7 Nicotinic Acetylcholine Receptor Signaling Inhibits Inflammasome Activation by Preventing Mitochondrial DNA Release

  • Ben Lu
  • Kevin Kwan
  • Yaakov A. Levine
  • Peder S. Olofsson
  • Huan Yang
  • Jianhua Li
  • Sonia Joshi
  • Haichao Wang
  • Ulf Andersson
  • Sangeeta S. Chavan
  • Kevin J. Tracey
Research Article

Abstract

The mammalian immune system and the nervous system coevolved under the influence of cellular and environmental stress. Cellular stress is associated with changes in immunity and activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, a key component of innate immunity. Here we show that α7 nicotinic acetylcholine receptor (α7 nAchR)-signaling inhibits inflammasome activation and prevents release of mitochondrial DNA, an NLRP3 ligand. Cholinergic receptor agonists or vagus nerve stimulation significantly inhibits inflammasome activation, whereas genetic deletion of α7 nAchR significantly enhances inflammasome activation. Acetylcholine accumulates in macrophage cytoplasm after adenosine triphosphate (ATP) stimulation in an α7 nAchR-independent manner. Acetylcholine significantly attenuated calcium or hydrogen oxide-induced mitochondrial damage and mitochondrial DNA release. Together, these findings reveal a novel neurotransmitter-mediated signaling pathway: acetylcholine translocates into the cytoplasm of immune cells during inflammation and inhibits NLRP3 inflammasome activation by preventing mitochondrial DNA release.

Supplementary material

10020_2014_2001350_MOESM1_ESM.pdf (981 kb)
Supplementary material, approximately 980 KB.

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© The Author(s) 2014

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Authors and Affiliations

  • Ben Lu
    • 1
    • 2
  • Kevin Kwan
    • 2
  • Yaakov A. Levine
    • 2
    • 3
  • Peder S. Olofsson
    • 2
  • Huan Yang
    • 2
  • Jianhua Li
    • 2
  • Sonia Joshi
    • 2
  • Haichao Wang
    • 4
  • Ulf Andersson
    • 5
  • Sangeeta S. Chavan
    • 2
  • Kevin J. Tracey
    • 2
  1. 1.Department of Hematology, The 3rd Xiangya HospitalCentral South UniversityChangsha, Hunan ProvinceP.R. China
  2. 2.Laboratory of Biomedical ScienceFeinstein Institute for Medical ResearchManhassetUSA
  3. 3.Setpoint MedicalManhassetUSA
  4. 4.Department of Emergency MedicineNorth Shore University HospitalManhassetUSA
  5. 5.Department of Women’s and Children’s HealthKarolinska InstitutetStockholmSweden

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