Myocyte TLR4 enhances enteric and systemic inflammation driving late murine endotoxic ileus

Bettina M. Buchholz, Richard A. Shapiro, Yoram Vodovotz, Timothy R. Billiar, Chhinder P. Sodhi, David J. Hackam, Anthony J. Bauer

Research output: Contribution to journalArticlepeer-review

Abstract

Myocytes are nonhemopoietic in origin and functionally essential in generating gastrointestinal motility. In endotoxemia, a rapid-onset nonhemopoietic mechanism potently triggers early ileus in a Toll-like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88)- dependent manner. Moreover, synergistically with hemopoietic cells, nonhemopoietic cells escalate late ileus via an IL-6 receptor-dependent inflammation-driven pathway. We therefore specifically investigated the role of myocytes in TLR4-triggered inflammation and ileus. TLR4+/+, TLR4-/-, bmTLR4+/+/TLR4-/- chimera, SM22-Cre+/- TLR4flox/flox, and selective myocyte TLR4-deficient (SM22-Cre-/- TLR4flox/flox) mice were injected intraperitoneally with purified lipopolysaccharide. SM22-driven Cre recombinase activity was selectively detected in cardiac, gastrointestinal, skeletal, and vascular myocytes, of small-sized vessels in a two-color fluorescent Cre reporter mouse. In contrast to nonhemopoietic TLR4 deficiency, deletion of myocyte TLR4 signaling prevented neither endotoxininduced suppression of spontaneous jejunal contractility in vitro nor early ileus in vivo at 6 h. Circulating plasma colony-stimulating factor 3 was greatly elevated during endotoxemia, independent of myocyte TLR4 signaling or time. TLR4 activation of myocytes contributed significantly to an early enteric IL-6 mRNA induction and systemic IL-6 release, as well as to a late increase in circulating chemokine (C-X-C motif) ligand 1 (CXCL1) and IL-17. Consequently, inhibition of myocyte TLR4 signaling allowed functional recovery of motility by preventing inflammation-driven late ileus at 24 h. Direct TLR4 activation of myocytes is not responsible for nonhemopoietic- mediated early ileus. However, myocytes are proinflammatory cells that potently drive enteric and systemic inflammation, subsequently fueling late mediator-triggered ileus. Specifically, the myocyte TLR4-dependent inflammatory signature of elevated plasma IL-6, CXCL1, and IL-17 is strongly associated with late rodent ileus.

Original languageEnglish (US)
Pages (from-to)G852-G862
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume308
Issue number10
DOIs
StatePublished - May 15 2015
Externally publishedYes

Keywords

  • Cre reporter IRG mouse
  • Gastrointestinal motility
  • Lipopolysaccharide

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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