Genetically-Defined Deficiency of Mannose-Binding Lectin Is Associated with Protection after Experimental Stroke in Mice and Outcome in Human Stroke

Genetically-Defined Deficiency of Mannose-Binding Lectin Is Associated with Protection after Experimental Stroke in Mice and Outcome in Human Stroke

The complement system is a major effector of innate immunity that has been involved in stroke brain damage. Complement activation occurs through the classical, alternative and lectin pathways. The latter is initiated by mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs). Here we investigated whether the lectin pathway contributes to stroke outcome in mice and humans.

Focal cerebral ischemia/reperfusion in MBL-null mice induced smaller infarctions, better functional outcome, and diminished C3 deposition and neutrophil infiltration than in wild-type mice. Accordingly, reconstitution of MBL-null mice with recombinant human MBL (rhMBL) enhanced brain damage. In order to investigate the clinical relevance of these experimental observations, a study of MBL2 and MASP-2 gene polymorphism rendering the lectin pathway dysfunctional was performed in 135 stroke patients. In logistic regression adjusted for age, gender and initial stroke severity, unfavourable outcome at 3 months was associated with MBL-sufficient genotype (OR 10.85, p = 0.008) and circulating MBL levels (OR 1.29, p = 0.04). Individuals carrying MBL-low genotypes (17.8%) had lower C3, C4, and CRP levels, and the proinflammatory cytokine profile was attenuated versus MBL-sufficient genotypes.

In conclusion, genetically defined MBL-deficiency is associated with a better outcome after acute stroke in mice and humans.

References
Alvaro Cervera1, Anna M. Planas2, Carles Justicia2, Xabier Urra1, Jens C. Jensenius3, Ferran Torres4,5, Francisco Lozano5,6*, Angel Chamorro1*

1 Comprehensive Stroke Center, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Medical School, University of Barcelona, Barcelona, Spain, 2 Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 3 Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark, 4 Clinical Pharmacology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Medical School, University of Barcelona, Barcelona, Spain, 5 Department of Cellular Biology, Immunology, and Neuroscience, Medical School, University of Barcelona, Barcelona, Spain, 6 Immunology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

Abstract
Background
The complement system is a major effector of innate immunity that has been involved in stroke brain damage. Complement activation occurs through the classical, alternative and lectin pathways. The latter is initiated by mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs). Here we investigated whether the lectin pathway contributes to stroke outcome in mice and humans.

Methodology/Principal Findings
Focal cerebral ischemia/reperfusion in MBL-null mice induced smaller infarctions, better functional outcome, and diminished C3 deposition and neutrophil infiltration than in wild-type mice. Accordingly, reconstitution of MBL-null mice with recombinant human MBL (rhMBL) enhanced brain damage. In order to investigate the clinical relevance of these experimental observations, a study of MBL2 and MASP-2 gene polymorphism rendering the lectin pathway dysfunctional was performed in 135 stroke patients. In logistic regression adjusted for age, gender and initial stroke severity, unfavourable outcome at 3 months was associated with MBL-sufficient genotype (OR 10.85, p = 0.008) and circulating MBL levels (OR 1.29, p = 0.04). Individuals carrying MBL-low genotypes (17.8%) had lower C3, C4, and CRP levels, and the proinflammatory cytokine profile was attenuated versus MBL-sufficient genotypes.

Conclusions/Significance
In conclusion, genetically defined MBL-deficiency is associated with a better outcome after acute stroke in mice and humans.

Citation: Cervera A, Planas AM, Justicia C, Urra X, Jensenius JC, et al. (2010) Genetically-Defined Deficiency of Mannose-Binding Lectin Is Associated with Protection after Experimental Stroke in Mice and Outcome in Human Stroke. PLoS ONE 5(2): e8433. doi:10.1371/journal.pone.0008433

Editor: Andreas Meisel, Charité Universitaetsmedizin Berlin, Germany

Received: September 25, 2009; Accepted: November 26, 2009; Published: February 3, 2010

Copyright: © 2010 Cervera et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: Financed in part by the European Community (FP7/2007-2013; grant agreement n° 201024), the Spanish Ministry of Education and Science (SAF2008-04515-CO2-01 to AMP), the non-profitable foundation ‘Fundación Melchor Colet’ to A.Ch., and the Spanish Network for the Research in Infectious Diseases (REIPI, RD06/0008/1013) to F.L. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. A. Cervera and X. Urra are recipients of grants from the Spanish Institute of Health Carlos III.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: Flozano@clinic.ub.es (FL); achamorro@ub.edu (AC)

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