Communication Between Enteric Neurons, Glia, and Nociceptors Underlies the Effects of Tachykinins on Neuroinflammation

Tachykinins are involved in the physiological regulation of gastrointestinal functions and contribute to gastrointestinal pathophysiology.The mechanisms mediating tachykinin signaling in the enteric nervous system are poorly understood.This study defines specific anatomic sites at which tachykinins activate signaling in neurons and glia and show that inhibition of such signaling promotes resolution of colitis and neuroinflammation. 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::Polr2a tm1(CAG-GCaMP5g,-tdTomato)Tvrd and Sox10CreER T2 ::Polr2a tm1(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::CreER T2þ/-/Rpl22 tm1.1Psam / 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.(