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

Comprehensive Stroke Center, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Medical School, University of Barcelona, Barcelona, Spain.
PLoS ONE (Impact Factor: 3.23). 02/2010; 5(2):e8433. DOI: 10.1371/journal.pone.0008433
Source: PubMed


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.

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    • "Studies of experimental and clinical stroke indicate that the complement system contributes to ischemic injury [13-15]. The collectin mannose-binding lectin (MBL) has been shown to play a central pathogenic role in ischemic injury through deposition and complement activation on ischemic endothelium [16-18]. SP-D does not activate complement, yet, serum SP-D levels were recently shown to correlate to dementia and augmented mortality [19], raising the possibility that SP-D may affect neurodegenerative and inflammatory processes in the brain. "
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    ABSTRACT: Background Crosstalk between the immune system in the brain and the periphery may contribute to the long-term outcome both in experimental and clinical stroke. Although, the immune defense collectin surfactant protein-D (SP-D) is best known for its role in pulmonary innate immunity, SP-D is also known to be involved in extrapulmonary modulation of inflammation in mice. We investigated whether SP-D affected cerebral ischemic infarction and ischemia-induced inflammatory responses in mice. Methods The effect of SP-D was studied by comparing the size of ischemic infarction and the inflammatory and astroglial responses in SP-D knock out (KO) and wild type (WT) mice subjected to permanent middle cerebral artery occlusion. SP-D mRNA production was assessed in isolated cerebral arteries and in the whole brain by PCR, and SP-D protein in normal appearing and ischemic human brain by immunohistochemistry. Changes in plasma SP-D and TNF were assessed by ELISA and proximity ligation assay, respectively. Results Infarct volumetric analysis showed that ablation of SP-D had no effect on ischemic infarction one and five days after induction of ischemia. Further, ablation of SP-D had no effect on the ischemia-induced increase in TNF mRNA production one day after induction of ischemia; however the TNF response to the ischemic insult was affected at five days. SP-D mRNA was not detected in parenchymal brain cells in either naïve mice or in mice subjected to focal cerebral ischemia. However, SP-D mRNA was detected in middle cerebral artery cells in WT mice and SP-D protein in vascular cells both in normal appearing and ischemic human brain tissue. Measurements of the levels of SP-D and TNF in plasma in mice suggested that levels were unaffected by the ischemic insult. Microglial-leukocyte and astroglial responses were comparable in SP-D KO and WT mice. Conclusions SP-D synthesis in middle cerebral artery cells is consistent with SP-D conceivably leaking into the infarcted area and affecting local cytokine production. However, there was no SP-D synthesis in parenchymal brain cells and ablation of SP-D had no effect on ischemic cerebral infarction.
    Journal of Neuroinflammation 07/2014; 11(1):123. DOI:10.1186/1742-2094-11-123 · 5.41 Impact Factor
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    • "Likewise, application of the therapeutic MASP-2 inhibitor mAb AbyD04211 revealed significant protection for cerebral IRI (Chrysanthou et al., unpublished). This finding is in good agreement with the recent report demonstrating that MBL null mice also show a significant degree of protection in an experimental mouse model of stroke (Cervera et al. 2010). An additional line of evidence, which underlines a critical role of the lectin pathway component MASP-2 in human I/R comes from a recent clinical study showing that MASP-2 levels are significantly decreased in acute MI patients compared to control (Zhang et al. 2011). "
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    ABSTRACT: Tissue injury and inflammation following ischemia and reperfusion of various organs have been recognized for many years. Many reviews have been written over the last several decades outlining the role of complement in ischemia/reperfusion injury. This short review provides a current state of the art knowledge on the complement pathways activated, complement components involved and a review of the clinical biologics/inhibitors used in the clinical setting of ischemia/reperfusion. This is not a complete review of the complement system in ischemia and reperfusion injury but will give the reader an updated view point of the field, potential clinical use of complement inhibitors, and the future studies needed to advance the field.
    Immunobiology 11/2012; 217(11):1026-33. DOI:10.1016/j.imbio.2012.07.024 · 3.04 Impact Factor
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    • "To our knowledge the role of MBL has not been investigated in a rodent model of CIN. However, the fact that local ischemia and reperfusion is at least in part responsible for the development of CIN [4], and that MBL aggravates tissue damage during I/R injury [9,11,12,15], suggests a role of MBL in the pathogenesis of contrast-induced acute kidney injury. "
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    ABSTRACT: Local renal ischemia is regarded as an important factor in the development of contrast-induced nephropathy (CIN). Mannose-binding lectin (MBL) is involved in the tissue damage during experimental ischemia/reperfusion injury of the kidneys. The aim of the present study was to investigate the association of MBL deficiency with radiocontrast-induced renal dysfunction in a large prospective cohort. 246 patients with advanced non-dialysis-dependent renal dysfunction who underwent radiographic contrast procedures were included in the study. Baseline serum MBL levels were analyzed according to the occurrence of a creatinine-based (increase of ≥0.5 mg/dL or ≥25% within 48 hours) or cystatin C-based (increase of ≥10% within 24 hours) CIN. The incidence of creatinine-based and cystatin C-based CIN was 6.5% and 24%, respectively. MBL levels were not associated with the occurrence of creatinine-based CIN. However, patients that experienced a cystatin C increase of ≥10% showed significantly higher MBL levels than patients with a rise of <10% (median 2885 (IQR 1193-4471) vs. 1997 (IQR 439-3504)ng/mL, p = 0.01). In logistic regression analysis MBL deficiency (MBL levels≤500 ng/ml) was identified as an inverse predictor of a cystatin C increase ≥10% (OR 0.34, 95% CI 0.15-0.8, p = 0.01). MBL deficiency was associated with a reduced radiocontrast-induced renal dysfunction as reflected by the course of cystatin C. Our findings support a possible role of MBL in the pathogenesis of CIN.
    BMC Nephrology 09/2012; 13(1):99. DOI:10.1186/1471-2369-13-99 · 1.69 Impact Factor
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