2014/12/05 by Vasile I. Pavlov, Ying Siow Tan, Ying S. Tan +5 · 17 citations
Immunology and Microbiology · Medicine · #Complement system in diseases #Coagulation, Bradykinin, Polyphosphates, and Angioedema #Blood Coagulation and Thrombosis Mechanisms
paper · pdf · doi:10.1016/j.ajpath.2014.10.015
Myocardial infarction and coagulation disorders are leading causes of disability and death in the world. An important role of the lectin complement pathway in myocardial infarction and coagulation has been demonstrated in mice genetically deficient in lectin complement pathway proteins. However, these studies are limited to comparisons between wild-type and deficient mice and lack the ability to examine reversal/inhibition of injury after disease establishment. We developed a novel mouse that expresses functional human mannose-binding lectin (MBL) 2 under the control of Mbl1 promoter. Serum MBL2 concentrations averaged approximately 3 μg/mL in MBL2+/+Mbl1−/− Mbl2−/− [MBL2 knock in (KI)] mice. Serum MBL2 level in MBL2 KI mice significantly increased after 7 (8 μg/mL) or 14 (9 μg/mL) days of hyperglycemia compared to normoglycemic mice (P < 0.001). Monoclonal antibody 3F8 inhibited C3 deposition on mannan-coated plates in MBL2 KI, but not wild-type, mice. Myocardial ischemia/reperfusion in MBL2 KI mice revealed that 3F8 preserved cardiac function and decreased infarct size and fibrin deposition in a time-dependent manner. Furthermore, 3F8 prevented ferric chloride–induced occlusive arterial thrombogenesis in vivo. MBL2 KI mice represent a novel animal model that can be used to study the lectin complement pathway in acute and chronic models of human disease. Furthermore, these novel mice demonstrate the therapeutic window for MBL2 inhibition for effective treatment of disease and its complications. Myocardial infarction and coagulation disorders are leading causes of disability and death in the world. An important role of the lectin complement pathway in myocardial infarction and coagulation has been demonstrated in mice genetically deficient in lectin complement pathway proteins. However, these studies are limited to comparisons between wild-type and deficient mice and lack the ability to examine reversal/inhibition of injury after disease establishment. We developed a novel mouse that expresses functional human mannose-binding lectin (MBL) 2 under the control of Mbl1 promoter. Serum MBL2 concentrations averaged approximately 3 μg/mL in MBL2+/+Mbl1−/− Mbl2−/− [MBL2 knock in (KI)] mice. Serum MBL2 level in MBL2 KI mice significantly increased after 7 (8 μg/mL) or 14 (9 μg/mL) days of hyperglycemia compared to normoglycemic mice (P < 0.001). Monoclonal antibody 3F8 inhibited C3 deposition on mannan-coated plates in MBL2 KI, but not wild-type, mice. Myocardial ischemia/reperfusion in MBL2 KI mice revealed that 3F8 preserved cardiac function and decreased infarct size and fibrin deposition in a time-dependent manner. Furthermore, 3F8 prevented ferric chloride–induced occlusive arterial thrombogenesis in vivo. MBL2 KI mice represent a novel animal model that can be used to study the lectin complement pathway in acute and chronic models of human disease. Furthermore, these novel mice demonstrate the therapeutic window for MBL2 inhibition for effective treatment of disease and its complications. The innate immune system plays an important role in host defense. The complement system, as a part of the innate immune system, is involved in protection against pathogens.1Janeway Jr., C.A. Medzhitov R. Innate immune recognition.Annu Rev Immunol. 2002; 20: 197-216Crossref PubMed Scopus (6367) Google Scholar The complement cascade can be activated/initiated through three distinct pathways: classic, alternative, and lectin. Lectin pathway (LP) activation is initiated by the presence of specific structures on microorganisms (bacterial, fungal, and some viral) binding to IgM or by changes in glycosylation patterns on compromised cells.2Collard C.D. Vakeva A. Morrissey M.A. Agah A. Rollins S.A. 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Mannose-binding lectin binds IgM to activate the lectin complement pathway in vitro and in vivo.Immunobiology. 2006; 211: 759-766Crossref PubMed Scopus (96) Google Scholar There are several pattern recognition molecules that may be involved in LP activation, such as mannose-binding lectin (MBL) 2 (Mbl1 and Mbl2 in mice), ficolins (1, 2, and 3), and collectin 11.6Liu H. Jensen L. Hansen S. Petersen S.V. Takahashi K. Ezekowitz A.B. Hansen F.D. Jensenius J.C. Thiel S. Characterization and quantification of mouse mannan-binding lectins (MBL-A and MBL-C) and study of acute phase responses.Scand J Immunol. 2001; 53: 489-497Crossref PubMed Scopus (83) Google Scholar, 7Hansen S. Selman L. Palaniyar N. Ziegler K. Brandt J. Kliem A. Jonasson M. Skjoedt M.O. Nielsen O. Hartshorn K. Jorgensen T.J.D. Skjodt K. Holmskov U. 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The role of mannose-binding lectin-associated serine protease-3 in activation of the alternative complement pathway.J Immunol. 2011; 187: 3751-3758Crossref PubMed Scopus (112) Google Scholar MBL plays a significant role as an initiation molecule that recognizes endogenous ligands after oxidative stress and tissue injury, ultimately leading to vascular wall remodeling, thrombogenesis, and other cellular injuries.2Collard C.D. Vakeva A. Morrissey M.A. Agah A. Rollins S.A. Reenstra W.R. Buras J.A. Meri S. Stahl G.L. Complement activation following oxidative stress: role of the lectin complement pathway.Am J Pathol. 2000; 156: 1549-1556Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, 5McMullen M.E. Hart M.L. Walsh M.C. Buras J. Takahashi K. Stahl G.L. Mannose-binding lectin binds IgM to activate the lectin complement pathway in vitro and in vivo.Immunobiology. 2006; 211: 759-766Crossref PubMed Scopus (96) Google Scholar, 18Jordan J.E. Montalto M.C. Stahl G.L. Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusion injury.Circulation. 2001; 104: 1413-1418Crossref PubMed Scopus (222) Google Scholar, 19Walsh M.C. Bourcier T. Takahashi K. Shi L. Busche M.N. Rother R.P. Solomon S.D. Ezekowitz R.A. Stahl G.L. Mannose-binding lectin is a of that myocardial and reperfusion Immunol. PubMed Scopus Google Scholar, M.N. Walsh M.C. M.E. Stahl G.L. Mannose-binding lectin plays a role in myocardial and reperfusion injury in a mouse model of 2008; PubMed Scopus Google Scholar, Takahashi K. Takahashi M. C. Fujita T. Stahl G.L. Mannose-binding lectin-associated serine protease-1 is a significant to coagulation in a model of occlusive Immunol. PubMed Scopus Google Scholar, Skjoedt A. Garred P. Stahl G.L. and complement myocardial injury and arterial PubMed Scopus Google Scholar the role of MBL in animal models of human disease has been limited to of wild-type mice to as as of mice with human There are to Mbl1 and and the study of the therapeutic window in animal models of human disease. Furthermore, the lack of to Mbl1 and Mbl2 not the study of disease or of after MBL complex activation in disease these and to the a novel human mouse that Mbl1 and We that MBL2+/+Mbl1−/− Mbl2−/− mice functional human MBL2 and LP activity to mice. Furthermore, antibody in the MBL2 KI mouse significantly the of myocardial myocardial infarct and myocardial fibrin deposition and occlusive thrombogenesis in vivo. and to the and under the and in the for the and of for the of the for the and of for the and of Google Scholar mouse to a MBL2 mouse in the Mbl1 human MBL2 a human MBL2 The by the and the recognition the used for of the and a used for of the The by and The used for the with and in four and two The mice with mice The and by the Mbl2−/− mouse and mice (8 to used as for MBL2 KI mice. Serum MBL2 concentrations in MBL2 KI mice in and as M.C. C.D. M. R.P. Stahl G.L. for functional of the binding lectin complement pathway to the level of C3 PubMed Scopus Google Scholar Serum MBL2 concentrations after 7 or 14 days of hyperglycemia as M. J. Stahl G.L. of mannose-binding lectin J Pathol. 180: Full Text Full Text PDF PubMed Scopus Google Scholar C3 deposition on mannan-coated plates as but with M.C. C.D. M. R.P. Stahl G.L. for functional of the binding lectin complement pathway to the level of C3 PubMed Scopus Google Scholar mouse or MBL2 KI mice on mannan-coated plates in the presence of μg/mL MBL2 or for the plates and mouse C3 deposition C3 and a antibody as M.C. C.D. M. R.P. Stahl G.L. for functional of the binding lectin complement pathway to the level of C3 PubMed Scopus Google Scholar for and in studies for the inhibition of MBL2 in the MBL2 KI mice of mouse by and 3F8 or for to 7 MBL2 concentrations as M.C. C.D. M. R.P. Stahl G.L. for functional of the binding lectin complement pathway to the level of C3 PubMed Scopus Google Scholar The myocardial and reperfusion model as Skjoedt A. Garred P. Stahl G.L. and complement myocardial injury and arterial PubMed Scopus Google Scholar, Stahl G.L. factor myocardial Immunol. 2009; 506-510Crossref PubMed Scopus Google Scholar of the to for or changes and used to and reperfusion and the and the heart and in or for infarct The following of MBL2 KI mice in the and two MBL2 KI or with or 3F8 as of reperfusion 3F8 after of reperfusion 3F8 after of reperfusion 3F8 or 3F8 Myocardial infarct size with as J.E. Montalto M.C. Stahl G.L. Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusion injury.Circulation. 2001; 104: 1413-1418Crossref PubMed Scopus (222) Google Scholar, 19Walsh M.C. Bourcier T. Takahashi K. Shi L. Busche M.N. Rother R.P. Solomon S.D. Ezekowitz R.A. Stahl G.L. Mannose-binding lectin is a of that myocardial and reperfusion Immunol. PubMed Scopus Google Scholar, Skjoedt A. Garred P. Stahl G.L. and complement myocardial injury and arterial PubMed Scopus Google Scholar, Agah A. Rollins S.A. L. Stahl G.L. Myocardial infarction and after myocardial and role of the complement components and inhibition by PubMed Scopus Google Scholar of the mice with The and the heart by The The heart through the with and with The and to with a in for of the heart between two with a and and with size by the of the and the The not significantly between not used to cardiac as M.C. Bourcier T. Takahashi K. Shi L. Busche M.N. Rother R.P. Solomon S.D. Ezekowitz R.A. Stahl G.L. Mannose-binding lectin is a of that myocardial and reperfusion Immunol. PubMed Scopus Google Scholar, M.N. Walsh M.C. M.E. Stahl G.L. Mannose-binding lectin plays a role in myocardial and reperfusion injury in a mouse model of 2008; PubMed Scopus Google Scholar after reperfusion with a with a to The mice with and on a in a by and of the and as M.C. Bourcier T. Takahashi K. Shi L. Busche M.N. Rother R.P. Solomon S.D. Ezekowitz R.A. Stahl G.L. Mannose-binding lectin is a of that myocardial and reperfusion Immunol. PubMed Scopus Google Scholar, M.N. Walsh M.C. M.E. Stahl G.L. Mannose-binding lectin plays a role in myocardial and reperfusion injury in a mouse model of 2008; PubMed Scopus Google Scholar The mouse ferric coagulation model used as Takahashi K. Takahashi M. C. Fujita T. Stahl G.L. Mannose-binding lectin-associated serine protease-1 is a significant to coagulation in a model of occlusive Immunol. PubMed Scopus Google Scholar, L. An model of ferric arterial for Full Text Full Text PDF PubMed Scopus Google Scholar, M.E. models of vascular PubMed Scopus Google Scholar mice in a and the by with a as Takahashi K. Takahashi M. C. Fujita T. Stahl G.L. Mannose-binding lectin-associated serine protease-1 is a significant to coagulation in a model of occlusive Immunol. PubMed Scopus Google Scholar with ferric to of the to the The after 3 and for The mice with 3) or 3F8 3 Myocardial and a the to by the in to for with in for by with in The in by a with in with H. H. A in mice with a PubMed Scopus Google in and in for The with and fibrin deposition with a and deposition by fibrin deposition in the the of fibrin deposition by the for fibrin the the of in with are as of and the used to demonstrate between A of and used to demonstrate between the two < MBL2 in and MBL2 KI mice mannan-coated plates MBL2 in and averaged There significant between and MBL2 the ability of MBL2 to as an acute phase protein under control of the Mbl1 MBL2 after hyperglycemia in mice. MBL2 significantly increased after 7 days μg/mL to or 14 days μg/mL to of hyperglycemia compared to normoglycemic to mice (P < 0.001). There significant in MBL2 after 7 or 14 days of of LP activation MBL2 with mouse complement in and MBL2 KI mice by C3 deposition on mannan-coated and MBL2 KI of mouse C3 on mannan-coated LP activation C3 deposition significantly inhibited by in or KI and the inhibition of mouse Mbl1 and Mbl2 in as as the human MBL2 complex in the MBL2 KI mice. 3F8 not mouse C3 deposition in However, C3 deposition MBL2 KI significantly inhibited by 3F8 to the level as These demonstrate that the LP in the of MBL2 KI mice to the as mice and demonstrate the to MBL2 in a mouse The of MBL2 in MBL2 KI mice 3F8 or after a 3F8 antibody inhibited MBL2 in a time-dependent a of mouse and inhibition of functional MBL2 a of or MBL2 inhibited for to 3 inhibition of MBL2 for to These demonstrate that inhibition of MBL2 can be a of Myocardial function after in MBL2 KI mice with 3F8 MBL2 KI mice a myocardial of approximately after is significantly decreased mice. MBL2 KI mice reperfusion with 3F8 mouse significantly prevented of cardiac and the of the not significantly the Furthermore, MBL2 KI mice with 3F8 mouse after or of reperfusion significantly against of cardiac function compared to the the of cardiac protection significantly that treatment reperfusion The demonstrate a protection of cardiac function after and the therapeutic window as reperfusion 3F8 the infarction and reperfusion injury, infarct We that treatment with 3F8 or after significantly MBL2 KI mice myocardial infarction compared with the control 2, and Myocardial to myocardial the four of mice are in to the myocardial infarction size significantly the treatment reperfusion of and infarct size increased treatment antibody myocardial as as myocardial injury a therapeutic for deposition after studies demonstrate a between LP activation and coagulation in Takahashi K. Takahashi M. C. Fujita T. Stahl G.L. Mannose-binding lectin-associated serine protease-1 is a significant to coagulation in a model of occlusive Immunol. PubMed Scopus Google Scholar, Skjoedt A. Garred P. Stahl G.L. and complement myocardial injury and arterial PubMed Scopus Google Scholar, K. Takahashi M. Ishida Y. Shi L. Fujita T. Stahl G.L. Mannose-binding lectin and its associated proteases (MASPs) coagulation and its is a factor in 2011; PubMed Scopus Google Scholar deposition increased the wall that to ischemia/reperfusion in control mice after of reperfusion and decreased after of reperfusion deposition vascular and of and by the to mice significantly deposition A and These the that MBL2 reduces reperfusion of the in to the in myocardial and infarct studies demonstrated that mice not an occlusive in to ferric compared to Takahashi K. Takahashi M. C. Fujita T. Stahl G.L. Mannose-binding lectin-associated serine protease-1 is a significant to coagulation in a model of occlusive Immunol. PubMed Scopus Google Scholar, Skjoedt A. Garred P. Stahl G.L. and complement myocardial injury and arterial PubMed Scopus Google Scholar, K. Takahashi M. Ishida Y. Shi L. Fujita T. Stahl G.L. Mannose-binding lectin and its associated proteases (MASPs) coagulation and its is a factor in 2011; PubMed Scopus Google Scholar MBL2 KI mice developed an occlusive after ferric treatment of MBL2 KI mice with 3F8 inhibited ferric chloride–induced These demonstrate that 3F8 significantly occlusive arterial thrombogenesis in in to ferric in the MBL2 KI These demonstrate that functional MBL in the MBL2 KI mouse are of human Furthermore, the serine proteases associated with the MBL2 complex are to thrombogenesis in and are inhibited by the role of complement in human disease by animal models has been with complement for in not with the complement components in other the of on with or by with or to the in the deficient with to the study of the functional MBL2 animal two functional MBL molecules Mbl1 and these or to chronic animal models of human disease or to a disease and the of complement inhibition on disease of these a mouse that expresses MBL2 under the control of the Mbl1 and (Mbl1 and by with the that MBL2 The MBL2 KI mice a that is not to a C3 deposition on mannan-coated plates inhibited by specific inhibition of MBL2 with 3F8 in MBL2 KI not The of LP inhibition by 3F8 the as that MBL2 is in the MBL2 KI studies demonstrated that a of 3F8 inhibited MBL2 for 7 3F8 is a mouse MBL2 that of 3F8 an immune and that MBL2 be inhibited for not in the MBL2 KI the of MBL2 KI mice and 3F8 an of to study the of MBL2 in chronic models of human disease. MBL2 in the MBL2 KI mouse approximately 3 is approximately the for Mbl1 in the H. Jensen L. Hansen S. Petersen S.V. Takahashi K. Ezekowitz A.B. Hansen F.D. Jensenius J.C. Thiel S. Characterization and quantification of mouse mannan-binding lectins (MBL-A and MBL-C) and study of acute phase responses.Scand J Immunol. 2001; 53: 489-497Crossref PubMed Scopus (83) Google Scholar We the for MBL2 to the Mbl1 that of the MBL2 and acute phase the Mbl2 expressed H. Jensen L. Hansen S. Petersen S.V. Takahashi K. Ezekowitz A.B. Hansen F.D. Jensenius J.C. Thiel S. Characterization and quantification of mouse mannan-binding lectins (MBL-A and MBL-C) and study of acute phase responses.Scand J Immunol. 2001; 53: 489-497Crossref PubMed Scopus (83) Google Scholar Serum MBL2 significantly increased in a hyperglycemia model such that MBL2 7 to 14 days of demonstrate that the Mbl1 MBL2 in the MBL2 KI mice We demonstrated that MBL is the molecule that activates complement and the LP after M.C. Bourcier T. 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PubMed Google mannose-binding lectin (MBL)-associated serine tissue tissue tissue in a mannose-binding lectin (MBL)-associated serine tissue tissue tissue developed a novel mouse under the control of the Mbl1 acute phase novel the of a role for MBL in by deposition and a therapeutic novel mouse the by to disease and MBL2 inhibition injury or its Furthermore, for the chronic models of disease can be for LP the MBL2 KI mouse be effective for and for the We Morrissey for the of these with MBL2 The human mannose-binding lectin (MBL) 2 the and the and for recognition for of the used to the for