Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury
Wilhelm J Schwaeble, Nicholas J Lynch, James E Clark, Michael Marber, Nilesh J Samani, Youssif Mohammed Ali, Thomas Dudler, Brian Parent, Karl Lhotta, Russell Wallis, Conrad A Farrar, Steven Sacks, Haekyung Lee, Ming Zhang, Daisuke Iwaki, Minoru Takahashi, Teizo Fujita, Clark E Tedford, Cordula M Stover, Wilhelm J Schwaeble, Nicholas J Lynch, James E Clark, Michael Marber, Nilesh J Samani, Youssif Mohammed Ali, Thomas Dudler, Brian Parent, Karl Lhotta, Russell Wallis, Conrad A Farrar, Steven Sacks, Haekyung Lee, Ming Zhang, Daisuke Iwaki, Minoru Takahashi, Teizo Fujita, Clark E Tedford, Cordula M Stover
Abstract
Complement research experienced a renaissance with the discovery of a third activation route, the lectin pathway. We developed a unique model of total lectin pathway deficiency, a mouse strain lacking mannan-binding lectin-associated serine protease-2 (MASP-2), and analyzed the role of MASP-2 in two models of postischemic reperfusion injury (IRI). In a model of transient myocardial IRI, MASP-2-deficient mice had significantly smaller infarct volumes than their wild-type littermates. Mice deficient in the downstream complement component C4 were not protected, suggesting the existence of a previously undescribed lectin pathway-dependent C4-bypass. Lectin pathway-mediated activation of C3 in the absence of C4 was demonstrated in vitro and shown to require MASP-2, C2, and MASP-1/3. MASP-2 deficiency also protects mice from gastrointestinal IRI, as do mAb-based inhibitors of MASP-2. The therapeutic effects of MASP-2 inhibition in this experimental model suggest the utility of anti-MASP-2 antibody therapy in reperfusion injury and other lectin pathway-mediated disorders.
Conflict of interest statement
Conflict of interest statement: C.E.T., B.P., and T.D. hold shares in Omeros Inc., Seattle, WA, which aims to market recombinant anti–MASP-2 mAb for therapeutic purposes.
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Source: PubMed