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

Jenny, Lorenz; Dobó, József; Gál, Péter; Schroeder, Verena

doi:10.1016/j.molimm.2015.02.014

Cited by 51 publications

(60 citation statements)

References 32 publications

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“…Reinforcing the hypothesized link between MASP‐1 and coagulation, thrombin inhibitors α2‐macroglobulin and anti‐thrombin III+heparin appeared to have the capability to inhibit MASP‐1 and ‐2 . MASP‐2 was linked to coagulation as well via its ability to cleave prothrombin and later studies have revealed that also MASP‐1 is a thrombin activator . Furthermore, the broad substrate specificity of MASP‐1 was found to include the thrombin‐activatable fibrinolysis inhibitor (TAFI) .…”

Section: Masp and Coagulation Cross‐talkmentioning

confidence: 84%

“…The observed in vivo effects of the lectin pathway on coagulation may be a reflection of the ability of MASP‐1 to cleave prothrombin and to a lesser degree other coagulation factors. It has been shown in vitro that MASP‐1 does not initiate clotting yet, once the clotting process is initiated, the dynamics of MASP‐1 very closely resembles that of thrombin . This delayed effect of MASP‐1 likely comes down to the need for activating thrombin …”

Section: Masp and Coagulation Cross‐talkmentioning

confidence: 99%

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A journey through the lectin pathway of complement—MBL and beyond

Garred

Genster

Pilely

et al. 2016

Immunological Reviews

323

302

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Mannose-binding lectin (MBL), collectin-10, collectin-11, and the ficolins (ficolin-1, ficolin-2, and ficolin-3) are soluble pattern recognition molecules in the lectin complement pathway. These proteins act as mediators of host defense and participate in maintenance of tissue homeostasis. They bind to conserved pathogen-specific structures and altered self-antigens and form complexes with the pentraxins to modulate innate immune functions. All molecules exhibit distinct expression in different tissue compartments, but all are found to a varying degree in the circulation. A common feature of these molecules is their ability to interact with a set of serine proteases named MASPs (MASP-1, MASP-2, and MASP-3). MASP-1 and -2 trigger the activation of the lectin pathway and MASP-3 may be involved in the activation of the alternative pathway of complement. Furthermore, MASPs mediate processes related to coagulation, bradykinin release, and endothelial and platelet activation. Variant alleles affecting expression and structure of the proteins have been associated with a variety of infectious and non-infectious diseases, most commonly as disease modifiers. Notably, the severe 3MC (Malpuech, Michels, Mingarelli, and Carnevale) embryonic development syndrome originates from rare mutations affecting either collectin-11 or MASP-3, indicating a broader functionality of the complement system than previously anticipated. This review summarizes the characteristics of the molecules in the lectin pathway.

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Section: Masp and Coagulation Cross‐talkmentioning

confidence: 84%

Section: Masp and Coagulation Cross‐talkmentioning

confidence: 99%

A journey through the lectin pathway of complement—MBL and beyond

Garred

Genster

Pilely

et al. 2016

Immunological Reviews

323

302

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“…MASP-1 can cleave high-molecular-weight kininogen to bradykinin, a vasoactive and nociceptive peptide [7]. It can also cleave prothrombin, FXIII and TAFI, thus MASP-1 can modulate the function of the clotting and fibrinolytic systems [8][9][10]. Moreover, active MASP-1 (both in native form complexed with MBL and as recombinant, rMASP-1) is able to cleave protease activated receptors (PAR1, 2 and 4), and this generates a proinflammatory signal in endothelial cells [11,12].…”

Section: Introductionmentioning

confidence: 99%

Complement MASP-1 enhances adhesion between endothelial cells and neutrophils by up-regulating E‐selectin expression

Jani

Schwaner

Kajdácsi

et al. 2016

Molecular Immunology

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Abbreviation: HUVEC, human umbilical vein endothelial cell; MBL, mannan-binding lectin; MASP, mannan-binding lectin-associated serine protease; PAR, protease-activated receptor. AbstractThe complement system and neutrophil granulocytes are indispensable in the immune response against extracellular pathogens such as bacteria and fungi. Endothelial cells also participate in antimicrobial immunity largely by regulating the homing of leukocytes through their cytokine production and their pattern of cell surface adhesion molecules. We have previously shown that mannan-binding lectin-associated serine protease-1 (MASP-1), a complement lectin pathway enzyme, is able to activate endothelial cells by cleaving protease activated receptors, which leads to cytokine production and enables neutrophil chemotaxis. Therefore, we aimed to investigate how recombinant MASP-1 (rMASP-1) can modify the pattern of P-selectin, E-selectin, ICAM-1, ICAM-2, and VCAM-1 adhesion molecules in human umbilical vein endothelial cells (HUVEC), and whether these changes can enhance the adherence between endothelial cells and neutrophil granulocyte model cells (differentiated PLB-985). We found that HUVECs activated by rMASP-1 decreased the expression of ICAM-2 and increased that of E-selectin, whereas ICAM-1, VCAM-1 and P-selectin expression remained unchanged. Furthermore, these changes resulted in increased adherence between differentiated PLB-985 cells and endothelial cells. Our finding suggests that complement MASP-1 can increase adhesion between neutrophils and endothelial cells in a direct fashion. This is in agreement with our previous finding that MASP-1 increases the production of pro-inflammatory cytokines (such as IL-6 and IL-8) and chemotaxis, and may thereby boost neutrophil functions. This newly described cooperation between complement lectin pathway and neutrophils via endothelial cells may be an effective tool to enhance the antimicrobial immune response.

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“…In contrast, the function of MASP-3 has been unclear. MASP-1 has relatively broad substrate specificity (8), and it was implicated that it has a role in several proinflammatory reactions (9,10) and coagulation (11). Both MASP-1 and MASP-3 were suggested to participate in pro-FD conversion to FD (12,13), and it was speculated that even the proenzyme form of MASP-3 might be able to perform this process (13).…”

mentioning

confidence: 99%

MASP-1 and MASP-2 Do Not Activate Pro–Factor D in Resting Human Blood, whereas MASP-3 Is a Potential Activator: Kinetic Analysis Involving Specific MASP-1 and MASP-2 Inhibitors

Oroszlán

Körtvely

Szakács

et al. 2016

The Journal of Immunology

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It had been thought that complement factor D (FD) is activated at the site of synthesis, and only FD lacking a propeptide is present in blood. The serum of mannose-binding lectin–associated serine protease (MASP)-1/3(−/−) mice contains pro-FD and has markedly reduced alternative pathway activity. It was suggested that MASP-1 and MASP-3 directly activate pro-FD; however, other experiments contradicted this view. We decided to clarify the involvement of MASPs in pro-FD activation in normal, as opposed to deficient, human plasma and serum. Human pro-FD containing an APPRGR propeptide was produced in insect cells. We measured its activation kinetics using purified active MASP-1, MASP-2, MASP-3, as well as thrombin. We found all these enzymes to be efficient activators, whereas MASP proenzymes lacked such activity. Pro-FD cleavage in serum or plasma was quantified by a novel assay using fluorescently labeled pro-FD. Labeled pro-FD was processed with t1/2s of ∼3 and 5 h in serum and plasma, respectively, showing that proteolytic activity capable of activating pro-FD exists in blood even in the absence of active coagulation enzymes. Our previously developed selective MASP-1 and MASP-2 inhibitors did not reduce pro-FD activation at reasonable concentration. In contrast, at very high concentration, the MASP-2 inhibitor, which is also a poor MASP-3 inhibitor, slowed down the activation. When recombinant MASPs were added to plasma, only MASP-3 could reduce the half-life of pro-FD. Combining our quantitative data, MASP-1 and MASP-2 can be ruled out as direct pro-FD activators in resting blood; however, active MASP-3 is a very likely physiological activator.

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

Cited by 51 publications

References 32 publications

A journey through the lectin pathway of complement—MBL and beyond

A journey through the lectin pathway of complement—MBL and beyond

Complement MASP-1 enhances adhesion between endothelial cells and neutrophils by up-regulating E‐selectin expression

MASP-1 and MASP-2 Do Not Activate Pro–Factor D in Resting Human Blood, whereas MASP-3 Is a Potential Activator: Kinetic Analysis Involving Specific MASP-1 and MASP-2 Inhibitors

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