TNF regulates leukocyte-endothelial cell interactions and microvascular dysfunction during immune complex-mediated inflammation.
1. The aim of this study was to assess directly the role of TNF in immune complex-induced leukocyte-endothelial cell interactions and microvascular dysfunction. 2. Intravital microscopy was used to examine immune complex-induced leukocyte rolling, adhesion and emigration and microvascular permeability in cremasteric postcapillary venules in wild-type and TNF(-/-) mice. The reverse passive Arthus (RPA) reaction was used to localize immune complex formation to the cremaster muscle. 3. In wild-type mice, immune complex deposition induced a reduction in leukocyte rolling velocity and increases in leukocyte adhesion and emigration. In TNF(-/-) mice, the immune complex-induced reduction in leukocyte rolling velocity was significantly attenuated, and leukocyte adhesion and emigration were also significantly reduced relative to responses in wild-type mice. 4. The alterations in TNF(-/-) mice were associated with decreased expression of endothelial P-selectin and VCAM-1, and an absence of E-selectin-dependent rolling normally seen in wild-type mice at the peak of the response. In addition, the level of immune complex-induced microvascular permeability was attenuated in TNF(-/-) mice. 5. These findings demonstrate that in immune complex-induced inflammation, TNF promotes leukocyte rolling and adhesive interactions, and entry of leukocytes into sites of immune complex deposition, in part via the increased expression and/or function of endothelial P-selectin, E-selectin and VCAM-1. In addition, this increase in leukocyte recruitment mediated by TNF correlates directly with an increase in microvascular injury.
Norman
M Ursula
MU
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, Vic., 3168, Australia.
Lister
Karyn J
KJ
Yang
Yuan H
YH
Issekutz
Andrew
A
Hickey
Michael J
MJ
D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology / Q000378:metabolism*; D002199:Capillary Permeability / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000936:Antigen-Antibody Complex; D014409:Tumor Necrosis Factor-alpha