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 antigenpresenting cells. As a consequence, TNFR1^-/- mice had strongly reducedmRNA 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 TNFproducing mast cells fully restored DTHR in these mice, signaling of mast cellderived TNF through TNFR1-expressing ECs is essential for the recruitment of leukocytes into sites of inflammation.