MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase.
MicroRNAs (miRNAs) contribute to both neuronal and immune cell fate, but their involvement in intertissue communication remained unexplored. The brain, via vagal secretion of acetylcholine (ACh), suppresses peripheral inflammation by intercepting cytokine production; therefore, we predicted that microRNAs targeting acetylcholinesterase (AChE) can attenuate inflammation. Here, we report that inflammatory stimuli induced leukocyte overexpression of the AChE-targeting miR-132. Injected locked nucleic acid (LNA)-modified anti-miR-132 oligonucleotide depleted miR-132 amounts while elevating AChE in mouse circulation and tissues. In transfected cells, a mutated 3'UTR miR-132 binding site increased AChE mRNA expression, whereas cells infected with a lentivirus expressing pre-miR-132 showed suppressed AChE. Transgenic mice overexpressing 3'UTR null AChE showed excessive inflammatory mediators and impaired cholinergic anti-inflammatory regulation, in spite of substantial miR-132 upregulation in brain and bone marrow. Our findings identify the AChE mRNA-targeting miR-132 as a functional regulator of the brain-to-body resolution of inflammation, opening avenues for study and therapeutic manipulations of the neuro-immune dialog.
Shaked
Iftach
I
Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
Meerson
Ari
A
Wolf
Yochai
Y
Avni
Ran
R
Greenberg
David
D
Gilboa-Geffen
Adi
A
Soreq
Hermona
H
D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology; D007421:Intestine, Small / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000494:pharmacology; D017384:Sequence Deletion; D015398:Signal Transduction; D015854:Up-Regulation
D008070:Lipopolysaccharides; C546976:MIRN132 microRNA, mouse; D035683:MicroRNAs; D009841:Oligonucleotides; D000110:Acetylcholinesterase; D000109:Acetylcholine