The control of the complement lectin pathway activation revisited: Both C1-inhibitor and antithrombin are likely physiological inhibitors, while α2-macroglobulin is not

Paréj, Katalin; Dobó, József; Závodszky, Péter; Gál, Péter

doi:10.1016/j.molimm.2013.01.009

Cited by 69 publications

(70 citation statements)

References 42 publications

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“…1). AT is known to interact with MASP-1, and the affinity is increased by heparin (31,32). Therefore, we measured MASP-1/AT complexes and found elevated levels in heparinized plasma compared with the other plasma types (Supplemental Fig.…”

Section: Establishing a Masp-1/c1-inh Assaymentioning

confidence: 91%

The Levels of the Lectin Pathway Serine Protease MASP-1 and Its Complex Formation with C1 Inhibitor Are Linked to the Severity of Hereditary Angioedema

Hansen

Csuka

Munthe-Fog

et al. 2015

The Journal of Immunology

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C1 inhibitor (C1-INH) is known to form complexes with the lectin complement pathway serine proteases MASP-1 and MASP-2. Deficiency of C1-INH is associated with hereditary angioedema (HAE), an autosomal inherited disease characterized by swelling attacks caused by elevated levels of bradykinin. MASP-1 was shown to cleave high m.w. kininogen into bradykinin; therefore, we hypothesized that MASP-1 levels and the quantity of MASP-1/C1-INH complexes might be associated with different paraclinical and clinical outcomes of HAE. We measured MASP-1 serum concentrations and endogenous MASP-1/C1-INH complex levels in 128 HAE patients and 100 controls. Relatively high levels of pre-existing MASP-1/C1-INH complexes were observed in normal serum, and we found that both the serum levels of MASP-1 and the complex formation between MASP-1 and C1-INH were significantly reduced in HAE patients compared with matched controls (p < 0.0001). The level of MASP-1 and MASP-1/C1-INH complexes in HE patients correlated with the level of C1-INH (p = 0.0009 and p = 0.0047, respectively), the level of C4 (p = 0.0084 and p < 0.0001, respectively), and the number of attacks in the year of blood sampling (p = 0.0075 and p = 0.0058, respectively). In conclusion, we show that MASP-1/C1-INH complexes circulate in normal human blood. The levels of MASP-1 and MASP-1/C1-INH complexes are reduced in HAE patients compared with controls. Both MASP-1 and MASP-1/C1-INH complexes are related to the degree of complement C4 consumption, as well as the severity of disease. These results suggest that MASP-1 may exert a previously unrecognized role in the pathophysiology of HAE.

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Section: Establishing a Masp-1/c1-inh Assaymentioning

confidence: 91%

The Levels of the Lectin Pathway Serine Protease MASP-1 and Its Complex Formation with C1 Inhibitor Are Linked to the Severity of Hereditary Angioedema

Hansen

Csuka

Munthe-Fog

et al. 2015

The Journal of Immunology

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“…C1-inh forms a covalent complex with MASP-1 (Davis et al, 2008;Paréj et al, 2013), possibly distorting its structure and preventing the access of MASP-1 to their receptors. In order to unambiguously prove that the proteolytic activity of MASP-1 is responsible for cell activation, we created a proteolytically inactive form of MASP-1 catalytic fragment, which has the conformation of the active protease.…”

Section: Proteolytically Inactive Forms Masp-1 Catalytic Fragments Domentioning

confidence: 99%

Serum MASP-1 in complex with MBL activates endothelial cells

Megyeri

Jani

Kajdácsi

et al. 2014

Molecular Immunology

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The complement system plays an important role in the induction of inflammation. In this study we demonstrate that the initiation complexes of the lectin pathway, consisting of mannose-binding lectin (MBL) and associated serine proteases (MASPs) elicit Ca 2+ signaling in cultured endothelial cells (HUVECs). This is in agreement with our previous resultsshowing that the recombinant catalytic fragment of MASP-1 activates endothelial cells by cleaving protease activated receptor 4. Two other proteases, MASP-2 and MASP-3 are also associated with MBL. Earlier we showed that recombinant catalytic fragment of MASP-2 cannot activate HUVECs, and in this study we demonstrate that the same fragment of MASP-3 has also no effect. We find the same to be the case if we use recombinant forms of the Nterminal parts of MASP-1 and MASP-2 which only contain non-enzymatic domains.Moreover, stable zymogen mutant form of MASP-1 was also ineffective to stimulate endothelial cells, which suggests that in vivo MASP-1 have the ability to activate endothelial cells directly as well as to activate the lectin pathway simultaneously. We show that among the components of the MBL-MASPs complexes only MASP-1 is able to trigger response in HUVECs and the proteolytic activity of MASP-1 is essential. Our results strengthen the view that MASP-1 plays a central role in the early innate immune response.

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“…This is supported by the fact that MASP-1 is more efficiently inhibited by antithrombin (in the presence of heparin) than by C1-inhibitor Parej et al, 2013). Due to its unusually wide substrate binding groove and the resulting broad substrate specificity -which is atypical among complement proteases -MASP-1 is able to interact with various targets outside the complement system.…”

Section: Introductionmentioning

confidence: 98%

MASP-1 of the complement system promotes clotting via prothrombin activation

Jenny

Dobó

Gál

et al. 2015

Molecular Immunology

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associated serine protease; MBL, mannose binding lectin; MCF, maximum clot firmness; MES, 2-(N-Morpholino)-ethanesulfonic acid; PAR4, protease activated receptor 4; PPP, platelet-poor plasma; PT-DP, Prothrombin-depleted plasma; PVDF, polyvinylidene difluoride; rMASP-1cf, MASP-1 catalytic fragment; SGMI, Schistocerca gregaria protease inhibitor (SGPI)-based MASPinhibitor; WB, whole blood. AbstractMannan-binding lectin-associated serine protease-1 (MASP-1), a protein of the complement lectin pathway, resembles thrombin in terms of structural features and substrate specificity, and it has been shown to activate coagulation factors. Here we studied the effects of MASP-1 on clot formation in whole blood (WB) and platelet-poor plasma (PPP) by thrombelastography and further elucidated the underlying mechanism. Cleavage of prothrombin by MASP-1 was investigated by SDS-PAGE and N-terminal sequencing of cleavage products. Addition of MASP-1 or thrombin to WB and PPP shortened the clotting time and clot formation time significantly compared to recalcified-only samples. The combination of MASP-1 and thrombin had additive effects. In a purified system, MASP-1 was able to induce clotting only in presence of prothrombin. Analysis of MASP-1-digested prothrombin confirmed that MASP-1 cleaves prothrombin at three cleavage sites. In conclusion, we have shown that MASP-1 is able to induce and promote clot formation measured in a global setting using the technique of thrombelastography. We further confirmed that MASP-1-induced clotting is dependent on prothrombin. Finally, we have demonstrated that MASP-1 cleaves prothrombin and identified its cleavage sites, suggesting that MASP-1 gives rise to an alternative active form of thrombin by cleaving at the cleavage site R393.

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The control of the complement lectin pathway activation revisited: Both C1-inhibitor and antithrombin are likely physiological inhibitors, while α2-macroglobulin is not

Cited by 69 publications

References 42 publications

The Levels of the Lectin Pathway Serine Protease MASP-1 and Its Complex Formation with C1 Inhibitor Are Linked to the Severity of Hereditary Angioedema

The Levels of the Lectin Pathway Serine Protease MASP-1 and Its Complex Formation with C1 Inhibitor Are Linked to the Severity of Hereditary Angioedema

Serum MASP-1 in complex with MBL activates endothelial cells

MASP-1 of the complement system promotes clotting via prothrombin activation

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