Regulation of colonic epithelial repair in mice by Toll-like receptors and hyaluronic acid

Gastroenterology. 2009 Dec;137(6):2041-51. doi: 10.1053/j.gastro.2009.08.055. Epub 2009 Sep 2.

Abstract

Background & aims: The protective component of the host response to dextran sodium sulfate (DSS)-induced colitis in the mouse is mediated through the activation of Toll-like receptor (TLR) 4, the induction of cyclooxygenase (COX)-2, and prostaglandin E(2) production. TLR4 ligands include bacterial lipopolysaccharide and hyaluronic acid, a component of the extracellular matrix. Our hypothesis is that hyaluronic acid, through TLRs, plays a protective role in the host response to DSS-induced colitis.

Methods: DSS (2.5%) was administered for 7 days in wild-type and MyD88(-/-) mice. The mice also received intraperitoneal hyaluronic acid. The expression of hyaluronic acid, COX-2, and macrophage inflammatory protein (MIP)-2 was evaluated by immunohistochemistry.

Results: DSS induced a marked increase in hyaluronic acid in the lamina propria of wild-type but not MyD88(-/-) mice. Treatment with DSS also induced the MyD88-dependent expression of hyaluronic acid synthases 2 and 3, enzymes involved in hyaluronic acid synthesis, in lamina propria macrophages. Exogenous hyaluronic acid induced the expression of tumor necrosis factor alpha, MIP-2, and COX-2 in the colon in a MyD88-dependent manner. In wild-type but not MyD88(-/-), TLR4(-/-), COX-2(-/-) mice, hyaluronic acid was protective against DSS-induced colitis. In wild-type mice, hyaluronic acid was therapeutic in established DSS-induced colitis.

Conclusions: Endogenous hyaluronic acid expression is markedly increased in DSS-induced colitis and preserves the epithelium through TLR activation and COX-2 expression. Furthermore, exogenous hyaluronic acid, through the activation of TLRs and the production of prostaglandin E(2) through COX-2, has protective effects in DSS-induced colitis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / metabolism*
  • Cell Proliferation*
  • Chemokine CXCL2 / metabolism
  • Colitis / chemically induced
  • Colitis / immunology
  • Colitis / metabolism
  • Colitis / pathology*
  • Colitis / prevention & control
  • Colon / immunology
  • Colon / metabolism
  • Colon / pathology*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Dextran Sulfate
  • Disease Models, Animal
  • Female
  • Glucuronosyltransferase / metabolism
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism
  • Hyaluronan Synthases
  • Hyaluronic Acid / administration & dosage
  • Hyaluronic Acid / metabolism*
  • Injections, Intraperitoneal
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology*
  • Ligands
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • Regeneration
  • Time Factors
  • Toll-Like Receptor 4 / deficiency
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation

Substances

  • Anti-Inflammatory Agents
  • Cd44 protein, mouse
  • Chemokine CXCL2
  • Cxcl2 protein, mouse
  • Hyaluronan Receptors
  • Ligands
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Hyaluronic Acid
  • Dextran Sulfate
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Glucuronosyltransferase
  • Has2 protein, mouse
  • Has3 protein, mouse
  • Hyaluronan Synthases