Journal
BLOOD
Volume 114, Issue 8, Pages 1696-1706Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-11-187682
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Funding
- Deutsche Forschungsgemeinschaft [SFB 685 A6, B6, C1 Bi 696/3-1, BI 696/5-1, Sch 897/3, SFB 773 Z]
- Wilhelm Sander-Stiftung [97.041.3]
- Deutsche Krebshilfe [10-1917-M02]
- National Institutes of Health [RO3AIO59791]
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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. (Blood. 2009; 114: 1696-1706)
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