Mannan‐binding lectin‐associated serine protease 2 is critical for the development of renal ischemia reperfusion injury and mediates tissue injury in the absence of complement C4

Asgari, Elham; Farrar, Conrad A.; Lynch, Nicholas J.; Ali, Youssif M.; Roscher, Silke; Stover, Cordula M.; Zhou, Wuding; Schwaeble, Wilhelm; Sacks, Steven H.

doi:10.1096/fj.13-246306

Cited by 75 publications

(93 citation statements)

References 48 publications

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“…This indicated that both of these molecules were essential for enabling the conversion of C3 into its active form and promoting C3d formation on the injured cells, suggesting that the lectin complement activation pathway plays a key role in initiating complement activation. By contrast, complement deposition from C4-deficient mouse serum was unrestrained compared with that detected in NMS ( Figure 8, A and B), suggesting that MASP-2 used the C4-bypass route to cleave C3 in this model (26,27).…”

Section: Cl-11 Mediates Tissue Injury Following Renal Stressmentioning

confidence: 90%

“…Our data suggest that the pathway of complement activation triggered by CL-11 on tubule cells used MASP-2, leading to cleavage of C3 via a C4-independent route. Complement activation that proceeds through MASP-2 but does not subsequently require C4 has been reported in several organ models of stress-induced injury including postischemic injury of the heart, intestine, and kidney (26,27). Since CL-11 is expressed within these organs (3,4,11), it is possible that CL-11-mediated lectin pathway activation underpins a common trigger mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…In that report, reduced but clearly measurable lectin pathway-dependent cleavage of C3 was detected and could be inhibited by either adding MASP-2 inhibitory Abs or fluid-phase ligands to block lectin pathway-recognition subcomponents. C4-independent activation of C3 that is mediated by MASP-2 has also been described in several models of ischemia-reperfusion injury (IRI) including postischemic kidney injury (26,27). Therefore, we examined the requirement for C4 in the present study as well as the need for CL-11 and MASP-2 in triggering complement activation on RTECs.…”

Section: Cl-11 Mediates Tissue Injury Following Renal Stressmentioning

confidence: 95%

See 2 more Smart Citations

Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury

Farrar¹,

Tran²,

Li³

et al. 2016

Journal of Clinical Investigation

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147

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Section: Cl-11 Mediates Tissue Injury Following Renal Stressmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Cl-11 Mediates Tissue Injury Following Renal Stressmentioning

confidence: 95%

See 1 more Smart Citation

Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury

Farrar¹,

Tran²,

Li³

et al. 2016

Journal of Clinical Investigation

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113

147

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“…Until now, these observations were attributed to the anticoagulatory effects of TFPI, but our results suggest that additional inhibitory effects of TFPI on complement activation may be important in these models. Therefore, additional studies are warranted to investigate the effect of rTFPI in disease models where the LP significantly contributes to the pathophysiology, such as ischemia/reperfusion injury and where a selective targeted inhibition of MASP-2 functional activity was shown to significantly reduce inflammatory tissue loss [17]. In sum, rTFPI may have a therapeutic impact beyond its anticoagulatory role to dampen complement-mediated tissue damage during disease, as an endogenous inhibitor of MASP-2.…”

Section: Discussionmentioning

confidence: 99%

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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“…[16][17][18][19] Moreover, complement deficiency or blockade was shown to limit postischemic reperfusion injury in various organs, and protect against acute renal transplant rejection. [20][21][22][23][24] Conflicting data exist on the deleterious versus protective role of the lectin pathway of complement activation in graft rejection, as well as in patient and graft outcomes after SOT. [25][26][27][28] Many of the available studies in kidney transplantation are either retrospective, involve small numbers of patients, or have analyzed outcomes under previous eras of immunosuppression and anti-infectious therapies.…”

mentioning

confidence: 99%

Polymorphisms in the lectin pathway of complement activation influence the incidence of acute rejection and graft outcome after kidney transplantation

Golshayan¹,

Wójtowicz²,

Bibert³

et al. 2016

Kidney International

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There are conflicting data on the role of the lectin pathway of complement activation and its recognition molecules in acute rejection and outcome after transplantation. To help resolve this we analyzed polymorphisms and serum levels of lectin pathway components in 710 consecutive kidney transplant recipients enrolled in the nationwide Swiss Transplant Cohort Study, together with all biopsy-proven rejection episodes and 1-year graft and patient survival. Functional mannose-binding lectin (MBL) levels were determined in serum samples, and previously described MBL2, ficolin 2, and MBL-associated serine protease 2 polymorphisms were genotyped. Low MBL serum levels and deficient MBL2 diplotypes were associated with a higher incidence of acute cellular rejection during the first year, in particular in recipients of deceased-donor kidneys. This association remained significant (hazard ratio 1.75, 95% confidence interval 1.18-2.60) in a Cox regression model after adjustment for relevant covariates. In contrast, there was no significant association with rates of antibodymediated rejection, patient death, early graft dysfunction or loss. Thus, results in a prospective multicenter contemporary cohort suggest that MBL2 polymorphisms result in low MBL serum levels and are associated with acute cellular rejection after kidney transplantation. Since MBL deficiency is a relatively frequent trait in the normal population, our findings may lead to individual risk stratification and customized immunosuppression.

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Mannan‐binding lectin‐associated serine protease 2 is critical for the development of renal ischemia reperfusion injury and mediates tissue injury in the absence of complement C4

Cited by 75 publications

References 48 publications

Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury

Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury

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

Polymorphisms in the lectin pathway of complement activation influence the incidence of acute rejection and graft outcome after kidney transplantation

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