MicroRNAs in the Cholinergic Anti-Inflammatory Pathway: Immunotherapy
Immunotherapy: Open Access was congratulating its authors of most cited articles. The article entitled “MicroRNAs in the Cholinergic Anti-Inflammatory Pathway: ProspectiveTherapeutic Targets for Inflammatory Diseases” which was written by Yang Sun and Xia Liu was mostly cited article which was published in 2016 from Department of Pharmacology, Second Military Medical University School of Pharmacy, Shanghai, China by Yang Sun and Xia Liu.
The article will be as follows: The host inflammatory response can be self-limited or progress toimmunological and inflammatory diseases. It has been well known thathumoral anti-inflammatory mechanisms, including IL-10, TGF-β1,glucocorticoids and other cytokine inhibitors, can protect tissueagainst cytokine-induced damage in humans. Recent advances haveidentified a brain to immune system mechanisms, termed cholinergicanti-inflammatory pathway (CAP). Briefly, the vagus nerve senses andconveys the inflammatory signal to the brain, and the brain, via vagalsecretion of acetylcholine (ACh) which binds a7 nicotinic receptors onmacrophages (α7nAchR), suppresses peripheral cytokine productionand guard against tissue damage. The brain maintains immunehomeostasis via in real time monitoring and adjusting theinflammatory response, and this regulation manner is quicker, effectiveand localized when compared to humoral ones. Activation of this‘‘cholinergic reflex’’ has been found effective in various inflammatorydisease such as sepsis, rheumatoid arthritis, Crohn’s disease, andcerebral and myocardial ischaemia. However, vagus nerve stimulationin humans is an invasive procedure and is not feasible under manycircumstances. Pharmacological activation, such as nicotine, a non-specific α7nAchR agonist, is associated with severe side effects andtoxicity. Novel specific and effective targets activating CAP are stillneeded for the therapeutic interventions in inflammatory diseases.MicroRNAs (miRNAs) are non-coding transcripts of 18-25nucleotides, and they usually target mRNAs to modulate geneexpression by 1.2 to 4.0 fold rather than acting as on-off switches forgenes. miRNAs have been found to contribute to both neuronal andimmune cell fate, but their involvement in the neuroimmuneinterface of CAP remains largely unknown. Several miRNAs assistingvagal cholinergic anti-inflammatory activity, named cholinomiRs, hasbeen identified only recently, especially miR-124 and miR-132.They are reported to be induced by LPS challenge and their treatmentcould potentiate the CAP and attenuate inflammation.α7nAChR is essential for the cholinergic anti-inflammatory action. Downstream signal molecules that link α7nAChR activation andpro-inflammatory cytokine production will be potential targets fortherapeutic interventions that modulate inflammatory responses.MiR-124 is reported to be induced after LPS and α7nAChR activation,which in turn targets signal transducer and activator of transcription 3(STAT3) and TNF-α converting enzyme (TACE) and reduces IL-6production and TNF-α release. MiR-124 knockdown abolished thenicotine’s cholinergic anti-inflammatory action in LPS-triggeredmacrophages and mice. Furthermore, miR-124 overexpression couldsignificantly increase the survival rate of mice that were given a lethaldose of LPS. Therefore, miR-124 might be a valuable target intreating sepsis. Moreover, miR-124 shows therapeutic potential inother inflammatory-related diseases. MiR-124 mediates the protectiverole of nicotine in DSS-induced mice colitis, and miR-124reduction promoted inflammation and pathogenesis in ulcerativecolitis patients. Abnormal expression of miR-124 is also found inrheumatoid arthritis (RA) patients and ankylosing spondylitis (AS)patients. Forced expression of miR-124 repressed adjuvant-inducedarthritis (AIA) in rats by decreasing synoviocyte proliferation,leukocyte infiltration, and cartilage or bone destruction throughsuppressing RANKL and NFATc1. MiR-124 overexpressionsuppresses experimental autoimmune encephalomyelitis (EAE) bydeactivating microglia, a kind of macrophages resident in the brainand spinal cord, via the C/EBP-α-PU.1 pathway . Microinjection ofmiR-124 into the peritoneum, which then be transported bymacrophages to the site of spinal cord injury, could decrease theinfiltration of macrophages and therefore ameliorate spinal cord injury. MiR-124 also shows its therapeutic effect in the treatment ofglioma, B-cell lymphomas and even liver cancers by regulating STAT3or other targets. Therefore, miR-124 is a promising candidatetarget for a broad spectrum of inflammatory diseases.
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