Global Autorecognition and Activation of Complement by Mannan-Binding Lectin in a Mouse Model of Type 1 Diabetes

Axelgaard, Esben; Østergaard, Jakob Appel; Haxha, Saranda; Thiel, Steffen; Hansen, Troels Krarup

doi:10.1155/2017/9403754

Cited by 9 publications

(12 citation statements)

References 49 publications

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“…Low MBL levels (such as in MBL deficiency) could do so by impairment of pathogen clearance (8,14,36) and reduced removal of atherogenic lipoproteins (10). High MBL levels could have this effect by amplifying a low-grade immune response through complement activation in an interplay with hyperglycemia (15,16). In support of these explanations, two cross-sectional studies (18,19) and one prospective study (17) have shown a U-shaped association of serum MBL with carotid intima-media thickness and low-grade inflammation, supporting the hypothesis of a dual role for MBL in the development of CVD.…”

Section: Discussionmentioning

confidence: 99%

“…Low levels (as in MBL deficiency) could impair pathogen clearance and reduce removal of atherogenic lipoproteins (10,14). High levels may amplify a low-grade immune response through complement activation, in particular if hyperglycemia is present (15,16). In support of this potential dual role, three studies (17)(18)(19), with two in patients with diabetes (17,18), have reported a U-shaped association of serum MBL levels with carotid intima-media thickness and lowgrade inflammation.…”

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confidence: 99%

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Mannose-Binding Lectin and Risk of Cardiovascular Events and Mortality in Type 2 Diabetes: A Danish Cohort Study

et al. 2020

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Mannose-binding lectin (MBL) is linked to risk of cardiovascular disease (CVD) in diabetes, but the nature of the association is unclear. We investigated the association between MBL and the risk of cardiovascular events (CVE) and all-cause mortality in type 2 diabetes. RESEARCH DESIGN AND METHODSIn a cohort study of 7,588 patients with type 2 diabetes, we measured serum MBL in 7,305 patients and performed MBL expression genotyping in 3,043 patients. We grouped serum MBL and MBL expression genotypes into three categories: low, intermediate, and high. Outcomes were CVE (myocardial infarction, stroke, coronary revascularization, unstable angina, or cardiovascular death) and allcause mortality. The association with outcomes was examined by spline and Cox regression analyses. RESULTSSerum MBL and CVE showed a U-shaped association. Compared with the intermediate serum MBL category, the adjusted hazard ratio (HR) for CVE was 1.82 (95% CI 1.34-2.46) for the low-MBL category and 1.48 (95% CI 1.14-1.92) for the high-MBL category. We found a similar U-shaped association for all-cause mortality, but with lower risk estimates. Compared with the intermediate MBL expression genotype, the adjusted HR for CVE was 1.40 (95% CI 0.87-2.25) for the lowexpression genotype and 1.44 (95% CI 1.01-2.06) for the high-expression genotype. MBL expression genotype was not associated with all-cause mortality. CONCLUSIONSBoth serum MBL and MBL expression genotype showed a U-shaped association with CVE risk in individuals with type 2 diabetes. Our findings suggest that serum MBL is a risk factor for CVD in this population.Mannose-binding lectin (MBL), also known as mannan-binding lectin, is a multifunctional serum protein primarily produced in the liver (1). It belongs to the lectin family of blood proteins and is instrumental in innate immunity (1), initiating the complement cascade via the lectin pathway and promoting pathogen clearance. In contrast to the classical complement pathway, which recognizes an antibody bound to its target, the lectin pathway starts with MBL binding to carbohydrate structures (e.g., patterns of mannose) on the surface of pathogens (1,2). Functional serum MBL levels

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Mannose-Binding Lectin and Risk of Cardiovascular Events and Mortality in Type 2 Diabetes: A Danish Cohort Study

et al. 2020

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“…Further, diabetes was associated with an increase in the autoreactivity activity of MBL in the kidney, further suggesting an activation of the lectin pathway in the diabetic kidney ( 13 , 14 , 111 ). More recently, in streptozotocin-induced diabetic BALB/c mice, albuminuria was worse in Daf knockout mice when compared with WT controls ( 9 ).…”

Section: Preclinical Datamentioning

confidence: 94%

The Complement Pathway: New Insights into Immunometabolic Signaling in Diabetic Kidney Disease

Tan

Snelson

Østergaard

et al. 2022

Antioxidants & Redox Signaling

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Significance: The metabolic disorder, diabetes mellitus, results in microvascular complications, including diabetic kidney disease (DKD), which is partly believe to involve disrupted energy generation in the kidney, leading to injury that is characterized by inflammation and fibrosis. An increasing body of evidence indicates that the innate immune complement system is involved in the pathogenesis of DKD; however, the precise mechanisms remain unclear. Recent Advances: Complement, traditionally thought of as the prime line of defense against microbial intrusion, has recently been recognized to regulate immunometabolism. Studies have shown that the complement activation products, Complement C5a and C3a, which are potent pro-inflammatory mediators, can mediate an array of metabolic responses in the kidney in the diabetic setting, including altered fuel utilization, disrupted mitochondrial respiratory function, and reactive oxygen species generation. In diabetes, the lectin pathway is activated via autoreactivity toward altered self-surfaces known as danger-associated molecular patterns, or via sensing altered carbohydrate and acetylation signatures. In addition, endogenous complement inhibitors can be glycated, whereas diet-derived glycated proteins can themselves promote complement activation, worsening DKD, and lending support for environmental influences as an additional avenue for propagating complement-induced inflammation and kidney injury. Critical Issues: Recent evidence indicates that conventional renoprotective agents used in DKD do not target the complement, leaving this web of inflammatory stimuli intact. Future Directions: Future studies should focus on the development of novel pharmacological agents that target the complement pathway to alleviate inflammation, oxidative stress, and kidney fibrosis, thereby reducing the burden of microvascular diseases in diabetes. Antioxid. Redox Signal . 37, 781–801.

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“…This in turn cleaves C3 to produce C5 convertase, which later enters the terminal pathway of complement activation to form a membrane attack complex (MAC) and lyse cells, resulting in impaired renal function, especially via tubulointerstitial damage (Henriksen et al, 2013;Zheng et al, 2018). After the cleavage of complement protein C3, the deposition of the released C3b fragment can also trigger a local inflammatory response, enhancing phagocytosis by activated macrophages and releasing various inflammatory cytokines and chemokines (C3a and C5a) (Axelgaard et al, 2017b). In addition, compared with a control group, the expression of MBL and nuclear factor-κB (NF-κB) was significantly increased in the glomeruli of DN rats, and the expression of MBL was positively correlated with the expression of NF-κB, which is involved in the development of DN (Yang et al, 2011).…”

Section: Mblmentioning

confidence: 99%

Roles of pattern recognition receptors in diabetic nephropathy

Zhou

Jiang

Zhao

et al. 2020

J. Zhejiang Univ. Sci. B

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Diabetic nephropathy (DN) is currently the most common complication of diabetes. It is considered to be one of the leading causes of end-stage renal disease (ESRD) and affects many diabetic patients. The pathogenesis of DN is extremely complex and has not yet been clarified; however, in recent years, increasing evidence has shown the important role of innate immunity in DN pathogenesis. Pattern recognition receptors (PRRs) are important components of the innate immune system and have a significant impact on the occurrence and development of DN. In this review, we classify PRRs into secretory, endocytic, and signal transduction PRRs according to the relationship between the PRRs and subcellular compartments. PRRs can recognize related pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), thus triggering a series of inflammatory responses, promoting renal fibrosis, and finally causing renal impairment. In this review, we describe the proposed role of each type of PRRs in the development and progression of DN.

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Global Autorecognition and Activation of Complement by Mannan-Binding Lectin in a Mouse Model of Type 1 Diabetes

Cited by 9 publications

References 49 publications

Mannose-Binding Lectin and Risk of Cardiovascular Events and Mortality in Type 2 Diabetes: A Danish Cohort Study

Mannose-Binding Lectin and Risk of Cardiovascular Events and Mortality in Type 2 Diabetes: A Danish Cohort Study

The Complement Pathway: New Insights into Immunometabolic Signaling in Diabetic Kidney Disease

Roles of pattern recognition receptors in diabetic nephropathy

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