α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release.
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.
Department of Hematology, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
Ben
B
Lu
Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
Kevin
K
Kwan
Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York, United States of America Setpoint Medical, Manhasset, New York, United States of America.
Yaakov A
YA
Levine
Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
Peder S
PS
Olofsson
Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
Huan
H
Yang
Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
Jianhua
J
Li
Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
Sonia
S
Joshi
Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York, United States of America.
Haichao
H
Wang
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Ulf
U
Andersson
Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
Sangeeta S
SS
Chavan
Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
Kevin J
KJ
Tracey
D000109:Acetylcholine / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003713:Dendritic Cells; D057809:HEK293 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D018679:Cholinergic Agonists; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D016207:Cytokines; D004272:DNA, Mitochondrial; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000255:Adenosine Triphosphate; D000109:Acetylcholine