Direct crosstalk between mast cell-TNF and TNFR1-expressing endothelia mediates local tissue inflammation

Blood. 2009 Aug 20;114(8):1696-706. doi: 10.1182/blood-2008-11-187682. Epub 2009 Jun 22.

Abstract

Signaling through tumor necrosis factor receptor 1 (TNFR1) controls bacterial infections and the induction of inflammatory Th1 cell-mediated autoimmune diseases. By dissecting Th1 cell-mediated delayed-type hypersensitivity responses (DTHRs) into single steps, we localized a central defect to the missing TNFR1 expression by endothelial cells (ECs). Adoptive transfer and mast cell knockin experiments into Kit(W)/Kit(W-v), TNF(-/-), and TNFR1(-/-) mice showed that the signaling defect exclusively affects mast cell-EC interactions but not T cells or antigen-presenting cells. As a consequence, TNFR1(-/-) mice had strongly reduced mRNA and protein expression of P-selectin, E-selectin, ICAM-1, and VCAM-1 during DTHR elicitation. In consequence, intravital fluorescence microscopy revealed up to 80% reduction of leukocyte rolling and firm adhesion in TNFR1(-/-) mice. As substitution of TNF(-/-) mice with TNF-producing mast cells fully restored DTHR in these mice, signaling of mast cell-derived TNF through TNFR1-expressing ECs is essential for the recruitment of leukocytes into sites of inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cells, Cultured
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology*
  • Haptens / adverse effects
  • Hypersensitivity, Delayed / chemically induced
  • Hypersensitivity, Delayed / genetics
  • Hypersensitivity, Delayed / immunology
  • Inflammation / etiology*
  • Inflammation / genetics
  • Inflammation / metabolism
  • Mast Cells / immunology
  • Mast Cells / metabolism
  • Mast Cells / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Picryl Chloride / adverse effects
  • Receptor Cross-Talk / physiology*
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / physiology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Cell Adhesion Molecules
  • Haptens
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Picryl Chloride