Neuronal responses to cytokine limits intestinal hypermotility
Inflammation results in increased gastrointestinal (GI) motility and diarrhea, but the mechanism remains unclear. Contrary to expectations, we found that neuronal responses to cytokine inhibited GI motility, as Nav1.8-Cre-mediated neuronal deletion of Jak1, a cytokine signaling intermediate, markedly increased GI motility at homeostasis. These cytokine-responsive neurons may reside in the enteric nervous system (ENS) based on the pattern of gene-deletion and GI motility induced by Nav1.8- and Trpv1-Cre. Cytokine receptors upstream of Jak1 that inhibit GI motility at homeostasis include IFNg and IL-10, but not IL-4 or IFNa. Whilst deficiency in cytokine inhibition of GI motility did not appear to affect the health of the mice at homeostasis, worse outcomes were observed after experimental DSS colitis. Thus, we speculate that IFNg and IL-10, cytokines associated with type 1 immune responses, may participate in a protective neuro-immune negative feedback loop to limit excessive GI motility during intestinal inflammation.
Inflammation results in increased gastrointestinal (GI) motility and diarrhea, but the mechanism remains unclear. Contrary to expectations, we found that neuronal responses to cytokine inhibited GI motility, as Nav1.8-Cre-mediated neuronal deletion of Jak1, a cytokine signaling intermediate, markedly increased GI motility at homeostasis. These cytokine-responsive neurons may reside in the enteric nervous system (ENS) based on the pattern of gene-deletion and GI motility induced by Nav1.8- and Trpv1-Cre. Cytokine receptors upstream of Jak1 that inhibit GI motility at homeostasis include IFNg and IL-10, but not IL-4 or IFNa. Whilst deficiency in cytokine inhibition of GI motility did not appear to affect the health of the mice at homeostasis, worse outcomes were observed after experimental DSS colitis. Thus, we speculate that IFNg and IL-10, cytokines associated with type 1 immune responses, may participate in a protective neuro-immune negative feedback loop to limit excessive GI motility during intestinal inflammation.
WASHINGTON UNIVERSITY SCHOOL OF MEDICINE