Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury

Schwaeble, Wilhelm; Lynch, Nicholas J.; Clark, James E.; Marber, Michael; Samani, Nilesh J.; Ali, Youssif M.; Dudler, Thomas; Parent, Brian; Lhotta, Karl; Wallis, Russell; Farrar, Conrad A.; Sacks, Steven H.; Lee, Haekyung; Zhang, Ming; Iwaki, Daisuke; Takahashi, Minoru; Fujita, Teizo; Tedford, Clark E.; Stover, Cordula M.

doi:10.1073/pnas.1101748108

Cited by 172 publications

(232 citation statements)

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“…In recent years, it has become apparent that activation of the LP of complement plays a prominent role in I/R injury, as shown in several human [2,11] and animal studies [3,12]. Our data suggest that TFPI can selectively block the LP, via interaction with MASP-2 and we therefore speculate that local upregulation of TFPI also protects endothelial cells from proinflammatory responses (i.e.…”

Section: Discussionsupporting

confidence: 61%

“…Notably, TFPI levels in plasma do not reflect the total amount of TFPI that may be relevant in vivo, since most TFPI is produced by endothelial cells [9]. Under certain (inflammatory) conditions TFPI expression is decreased, for example, during sepsis [10] which could likely increase the LP activation.In recent years, it has become apparent that activation of the LP of complement plays a prominent role in I/R injury, as shown in several human [2,11] and animal studies [3,12]. Our data suggest that TFPI can selectively block the LP, via interaction with MASP-2 and we therefore speculate that local upregulation of TFPI also protects endothelial cells from proinflammatory responses (i.e.…”

supporting

confidence: 61%

“…This detrimental role of the LP in I/R injury has been confirmed in mice by selectively targeting MASP-2. MASP-2 knockout mice were protected from both gastrointestinal and myocardial I/R injury [3]. Together, these data indicate an important role for MASP-2 in aggravating cell damage in ischemic tissues.…”

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confidence: 62%

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TFPI inhibits lectin pathway of complement activation by direct interaction with MASP‐2

et al. 2014

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The lectin pathway (LP) of complement has a protective function against invading pathogens. Recent studies have also shown that the LP plays an important role in ischemia/reperfusion (I/R)-injury. MBL-associated serine protease (MASP)-2 appears to be crucial in this process. The serpin C1-inhibitor is the major inhibitor of MASP-2. In addition, aprotinin, a Kunitz-type inhibitor, was shown to inhibit MASP-2 activity in vitro.In this study we investigated whether the Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI) is also able to inhibit MASP-2. Ex vivo LP was induced and detected by C4-deposition on mannan-coated plates. The MASP-2 activity was measured in a fluid-phase chromogenic assay. rTFPI in the absence or presence of specific monoclonal antibodies was used to investigate which TFPI-domains contribute to MASP-2 inhibition. Here, we identify TFPI as a novel selective inhibitor of MASP-2, without affecting MASP-1 or the classical pathway proteases C1s and C1r. Kunitz-2 domain of TFPI is required for the inhibition of MASP-2. Considering the role of MASP-2 in complement-mediated I/R-injury, the inhibition of this protease by TFPI could be an interesting therapeutic approach to limit the tissue damage in conditions such as cerebral stroke, myocardial infarction or solid organ transplantation.Keywords: Complement-coagulation crosstalk r Complement inhibition r MASP-2 r TFPI Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe complement system comprises over 30 different plasma proteins. The complement system consists of three activation pathways, each differing in their recognition mechanism while Correspondence: Mischa P. Keizer e-mail: m.keizer@sanquin.nl converging in a common terminal pathway at the level of complement component 3 (C3). The antibody-dependent classical pathway (CP) initiates the complement system via the binding of C1q to antibodies. Binding to specific sugar motifs by mannan-binding lectins (MBLs) or one of the ficolins activates the lectin pathway (LP) by subsequent activation of the MBL-associated serine proteases (MASPs). The alternative pathway activates spontaneously on surfaces that lack complement regulatory proteins and acts as amplification route for the other two pathways.www.eji-journal.eu Eur. J. Immunol. 2015. 45: 544-550 Innate immunity 545Besides the LP role as first line of defense against invading pathogens, by opsonization and induction of an inflammatory response, recent studies have shown that the LP also plays a prominent role in ischemia/reperfusion (I/R) injury. MBL-deficiency appears to be protective in human myocardial infarction [1], gastrointestinal I/R injury [1], and stroke [2]. This detrimental role of the LP in I/R injury has been confirmed in mice by selectively targeting MASP-2. MASP-2 knockout mice were protected from both gastrointestinal and myocardial I/R injury [3]. Together, these data indicate an important role for MASP-2 in aggravating cell damage in ischemi...

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Section: Discussionsupporting

confidence: 61%

supporting

confidence: 61%

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TFPI inhibits lectin pathway of complement activation by direct interaction with MASP‐2

et al. 2014

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“…Although our results in the elastase-induced AAA model indicate that AP activity may be the only activation pathway essential for the disease phenotype (12), it remains possible that the LP can still play a role in AAA development. A C2-dependent C4-bypass LP was recently described (31), and the contribution of this pathway to AAA formation in this model is currently being evaluated. Alternatively, the prominent contribution of the AP in our model system may be explained by the fact that we focused on the early initiating events of aneurysm development, whereas the human tissue samples were obtained at late-stage disease.…”

Section: Discussionmentioning

confidence: 99%

Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm

Zhou

Yan

Stover

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Abdominal aortic aneurysm (AAA) is a complex inflammatory vascular disease. There are currently limited treatment options for AAA when surgery is inapplicable. Therefore, insights into molecular mechanisms underlying AAA pathogenesis may reveal therapeutic targets that could be manipulated pharmacologically or biologically to halt disease progression. Using an elastase-induced AAA mouse model, we previously established that the complement alternative pathway (AP) plays a critical role in the development of AAA. However, the mechanism by which complement AP is initiated remains undefined. The complement protein properdin, traditionally viewed as a positive regulator of the AP, may also initiate complement activation by binding directly to target surfaces. In this study, we sought to determine whether properdin serves as a focal point for the initiation of the AP complement activation in AAA. Using a properdin loss of function mutation in mice and a mutant form of the complement factor B protein that produces a stable, properdinfree AP C3 convertase, we show that properdin is required for the development of elastase-induced AAA in its primary role as a convertase stabilizer. Unexpectedly, we find that, in AAA, natural IgG antibodies direct AP-mediated complement activation. The absence of IgG abrogates C3 deposition in elastase-perfused aortic wall and protects animals from AAA development. We also determine that blockade of properdin activity prevents aneurysm formation. These results indicate that an innate immune response to self-antigens activates the complement system and initiates the inflammatory cascade in AAA. Moreover, the study suggests that properdintargeting strategies may halt aneurysmal growth.

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“…MBL-associated serine proteases (MASP-1,2 and 3) are proteolytic enzymes that bind to collectins and ficolins to initiate complement activation. MASP-2 is notable in that it is able to mediate cleavage of C3 without C4 [51]. MBL has been described to be internalised by renal proximal tubuloepithelial cells in organ reperfusion whereby they are destroyed by apoptosis in a murine model [52].…”

Section: Complement Activation Pathways In Ir Injurymentioning

confidence: 99%

Complement—here, there and everywhere, but what about the transplanted organ?

Montero

Sacks

Smith

2016

Seminars in Immunology

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The part of the innate immune system that communicates and effectively primes the adaptive immune system was termed "complement" by Ehrlich to reflect its complementarity to antibodies having previously been described as "alexine" (i.e protective component of serum) by Buchner and Bordet. It has been established that complement is not solely produced systemically but may have origin in different tissues where it can influence organ specific functions that may affect the outcome of transplanted organs. This review looks at the role of complement in particular to kidney transplantation. We look at current literature to determine whether blockade of the peripheral or central compartments of complement production may prevent ischaemic reperfusion injury or rejection in the transplanted organ.We also review new therapeutics that have been developed to inhibit components of the complement cascade with varying degrees of success leading to an increase in our understanding of the multiple triggers of this complex system. In addition, we consider whether biomarkers in this field are effective markers of disease or treatment. Word count 169

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Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury

Cited by 172 publications

References 54 publications

TFPI inhibits lectin pathway of complement activation by direct interaction with MASP‐2

TFPI inhibits lectin pathway of complement activation by direct interaction with MASP‐2

Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm

Complement—here, there and everywhere, but what about the transplanted organ?

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