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

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

Author information

1
Department of Dermatology, Eberhard Karls University, Tübingen, Germany. manfred.kneilling@med.unituebingen.de

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.

PMID:
19546478
PMCID:
PMC2731644
DOI:
10.1182/blood-2008-11-187682
[Indexed for MEDLINE]
Free PMC Article

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