Mac-1 signaling via Src-Family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy

Immunity 2006 25:271-283

Speaker:徐英展                            Time: 2006/10/11 15:10~16:00

Commentator:林以行 老師                   Place: Room 601

Abstract:

Neutrophils play a unique role in inflammation in which CD18 integrins are involved in this process. Blockade of CD18 integrins-mediated neutrophil recruitment would reduce the influx of neutrophils into inflammation site. Other than neutrophil chemotaxis, engagement of CD18 integrins also signals activation of neutrophil effector function (ROS production and degranulation)¹. Mac-1, a predominant CD18 integrin on neutrophil, is postulated to play a very important role in neutrophil activation². Activated neutrophil can kill microbes by phagocytosis or extracellular release of ROS and proteinases. These released products due to degranulation contribute to tissue damage during inflammation. Although in vitro studies have delineated the signaling cascades responsible for CD18integrin-mediated adhesion, degranulation, and ROS production. It’s difficult to sort out the relative contribution of integrin alone to the neutrophil functioning in vivo. Using a local Shwartzman-like reaction model that produces histopathologic lesions of thrombohemorrhagic vasculitis, the authors showed that Mac-1 functions in the activation of neutrophil effector functions and is required for hemorrhagic lesion development. After interaction of Mac-1 on neutrophils with complement C3 deposited within the vessel wall leads to an intracellular signaling pathway involving Src-family and Syk kinase. The stimulation of localized degranulation would cause neutrophil elastase release that promotes vascular injury contributed to tissue hemorrhage.

Reference:

1.Harris, E.S. et al. The leukocyte integrins. J. Biol. Chem. 2000, 275: 23409-23412

2.Tang, T. et al. A role for Mac-1(CD11b/CD18) in immune complex-stimulated neutrophil function in vivo:Mac-1 deficiency abrogates sustained Fcgamma receptor –dependent neutrophil adhesion and complement-dependent proteinuria in acute glomeruloneohritis. J. Exp. Med.1997, 186:1853-1863.