Abstract
Terminal complement membrane attack complex (MAC) formation is induced initially by C5b, followed by the sequential condensation of the C6, C7, C8. Polymerization of C9 to the C5b-8 complex forms the C5b-9 (or MAC). The C5b-9 forms lytic or non lytic pores in the cell membrane destroys membrane integrity. The biological functionalities of MAC has been previously investigated by using either the mice deficient in C5 and C6, or MAC’s regulator CD59. However, there is no available C9 deficient mice (mC9−/−) for directly dissecting the role of C5b-9 in the pathogenesis of human diseases. Further, since C5b-7 and C5b-8 complexes form non lytic pore, it may also plays biological functionality. To better understand the role of terminal complement cascades, here we report a successful generation of mC9−/−. We demonstrated that lack of C9 attenuates anti-erythrocyte antibody-mediated hemolysis or LPS-induced acute shock. Further, the rescuing effect on the acute shock correlates with the less release of IL-1β in mC9−/−, which is associated with suppression of MAC-mediated inflammasome activation in mC9−/−. Taken together, these results not only confirm the critical role of C5b-9 in complement-mediated hemolysis and but also highlight the critical role of C5b-9 in inflammasome activation.
Highlights
Cell-bound C4b and C3b by the serum protease factor[7]
We report the successful generation of mC9−/− mice and demonstrate that the lack of C9 attenuates anti-erythrocyte antibody-mediated hemolysis in vitro and in vivo
These results indicate that the C5b-9 complex is the most important among the terminal complement complexes
Summary
Cell-bound C4b and C3b by the serum protease factor[7]. CD59 is the most important membrane inhibitor, which restricts C5b-9 formation by preventing C9 incorporation and polymerization[1,2,3,4]. Formation of the MAC at a sublytic concentration in a cell membrane in vivo activates signaling cascades[14] and releases inflammatory mediators, leading to the activation of nucleated cells and mediating cellular processes such as proliferation, inflammation, and thrombosis[15,16]. The contribution of C5b-9-induced IL-1βto the pathogenesis of human diseases, as modeled in animal systems, remains to be investigated It has been recognized for over thirty years that the C5b-7 and C5b-8 complexes are able to form a nonlytic pore, thereby mediating a hemolytic effect, killing bacteria and triggering the activation of signaling pathways in vitro, their biological function and relevance remain to be determined in vivo[19,20,21]. These results confirm the critical role of C5b-9 in complement-mediated hemolysis and highlight the critical role of C5b-9-induced inflammasome activation in LPS-induced shock
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