Direct crosstalk between mast cell-TNF and TNFR1-expressing endothelia mediates local tissue inflammation.
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.
Kneilling
Manfred
M
Department of Dermatology, Eberhard Karls University, Tübingen, Germany. manfred.kneilling@med.unituebingen.de
Mailhammer
Reinhard
R
Hültner
Lothar
L
Schönberger
Tanja
T
Fuchs
Kerstin
K
Schaller
Martin
M
Bukala
Daniel
D
Massberg
Steffen
S
Sander
Christian A
CA
Braumüller
Heidi
H
Eichner
Martin
M
Maier
Konrad L
KL
Hallmann
Rupert
R
Pichler
Bernd J
BJ
Haubner
Roland
R
Gawaz
Meinrad
M
Pfeffer
Klaus
K
Biedermann
Tilo
T
Röcken
Martin
M
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006241:Haptens / Q000009:adverse effects; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010853:Picryl Chloride / Q000009:adverse effects; D020239:Receptor Cross-Talk / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D015815:Cell Adhesion Molecules; D006241:Haptens; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D010853:Picryl Chloride