TRPV1 Sensory Neurons and Enteric Glia in ENS Link Tachykinins to Neuroinflammation and Nociception
| Autor: | Fievos L. Christofi |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Nociception DMEM Dulbecco's modified Eagle medium FGID functional gastrointestinal disorder Enteric Nervous System Mice 0302 clinical medicine Medicine Gliosis Original Research Neurons DNBS dinitrobenzene sulfonic acid Gastroenterology Ca2+ calcium Receptors Neurokinin-2 Colitis GI gastrointestinal mRNA messenger RNA medicine.anatomical_structure Editorial IPAN intrinsic primarily afferent neuron Neuroglia 030211 gastroenterology & hepatology Female TRPV1 transient receptor potential vanilloid-1 EFS electrical field stimulation Sensory Receptor Cells TRPV1 TRPV Cation Channels Sensory system Mice Transgenic BzATP 2’(3’)-O-(4-benzoylbenzoyl)adenosine 5’-triphosphate triethylammonium salt NKA neurokinin A 03 medical and health sciences Tachykinins Glia MSU Michigan State University Animals Humans LMMP longitudinal muscle–myenteric plexus NK1R neurokinin-1 receptor Neuroinflammation SP substance P Neurokinins ENS enteric nervous system Hepatology Extramural business.industry GFAP glial fibrillary acidic protein Mice Inbred C57BL Disease Models Animal Cx43 connexin-43 030104 developmental biology nervous system Enteric nervous system NK2R neurokinin-2 receptor business Neuroscience HA hemagglutinin |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| Popis: | Background & Aims Tachykinins are involved in physiological and pathophysiological mechanisms in the gastrointestinal tract. The major sources of tachykinins in the gut are intrinsic enteric neurons in the enteric nervous system and extrinsic nerve fibers from the dorsal root and vagal ganglia. Although tachykinins are important mediators in the enteric nervous system, how they contribute to neuroinflammation through effects on neurons and glia is not fully understood. Here, we tested the hypothesis that tachykinins contribute to enteric neuroinflammation through mechanisms that involve intercellular neuron-glia signaling. Methods We used immunohistochemistry and quantitative real-time polymerase chain reaction, and studied cellular activity using transient-receptor potential vanilloid-1 (TRPV1)tm1(cre)Bbm/J::Polr2atm1(CAG-GCaMP5g,-tdTomato)Tvrd and Sox10CreERT2::Polr2atm1(CAG-GCaMP5g,-tdTomato)Tvrd mice or Fluo-4. We used the 2,4-di-nitrobenzene sulfonic acid (DNBS) model of colitis to study neuroinflammation, glial reactivity, and neurogenic contractility. We used Sox10::CreERT2+/-/Rpl22tm1.1Psam/J mice to selectively study glial transcriptional changes. Results Tachykinins are expressed predominantly by intrinsic neuronal varicosities whereas neurokinin-2 receptors (NK2Rs) are expressed predominantly by enteric neurons and TRPV1-positive neuronal varicosities. Stimulation of NK2Rs drives responses in neuronal varicosities that are propagated to enteric glia and neurons. Antagonizing NK2R signaling enhanced recovery from colitis and prevented the development of reactive gliosis, neuroinflammation, and enhanced neuronal contractions. Inflammation drove changes in enteric glial gene expression and function, and antagonizing NK2R signaling mitigated these changes. Neurokinin A–induced neurodegeneration requires glial connexin-43 hemichannel activity. Conclusions Our results show that tachykinins drive enteric neuroinflammation through a multicellular cascade involving enteric neurons, TRPV1-positive neuronal varicosities, and enteric glia. Therapies targeting components of this pathway could broadly benefit the treatment of dysmotility and pain after acute inflammation in the intestine. Graphical abstract |
| Databáze: | OpenAIRE |
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