Emerging role of chemokine CC motif ligand 4 related mechanisms in diabetes mellitus and cardiovascular disease: friends or foes?

Chang, Ting‐Ting; Chen, Jaw Wen

doi:10.1186/s12933-016-0439-9

Cited by 82 publications

(77 citation statements)

References 120 publications

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“…Chemokines play essential roles in local in ammation, by attracting immune cells to the site of injury or in ammation (28)(29)(30). Previous studies have reported CCL2 levels to be independent predictors of cardiovascular events (29,30), and coherently we found CCL2 to be increased in participants with CAN.…”

Section: Chemotactic Cytokines Are Not Associated With Cardiovascularsupporting

confidence: 84%

Circulating Inflammatory Markers are Inversely Associated with Heart Rate Variability Measures in type 1 Diabetes

Wegeberg

Okdahl

Fløyel

et al. 2020

Preprint

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Background A neuro-immune communication exists, and compiling evidence suggests that diabetic neuropathy and systemic inflammation are linked. Our aims were 1) to investigate biomarkers of the ongoing inflammation processes including cytokines, adhesion molecules and chemokines, and 2) to associate the findings with cardiovascular autonomic neuropathy in type 1 diabetes by measuring heart rate variability and cardiac vagal tone.Methods We included 104 adults with type 1 diabetes. Heart rate variability, time- and frequency domains, were calculated from a 24-hour Holter electrocardiogram, while cardiac vagal tone was determined from a 5-minute electrocardiogram. Cytokines (interleukin (IL)-1α, IL-4, IL-12p70, IL-13, IL-17 and tumor necrosis factor (TNF)-α), adhesion molecules (E-selectin, P-selectin and intercellular adhesion molecule (ICAM)-1) and chemokines (chemokine (C-C motif) ligand (CCL)2, CCL3, CCL4 and C-X-C motif chemokine (CXCL)10) were assessed using a Luminex multiplexing technology. Associations between concentrations of inflammatory biomarkers and continuous variables of heart rate variability and cardiac vagal tone were estimated using multivariable linear regression adjusting for age, sex, disease duration and smoking.Results Participants with the presence of cardiovascular autonomic neuropathy had higher systemic levels of IL-1α, IL-4, CCL2 and E-selectin, than those without cardiovascular autonomic neuropathy. IL-1α, IL-4, IL-12, TNF-α and E-selectin were inversely associated with both sympathetic and parasympathetic heart rate variability measures (p>0.01).Conclusion Our results show that several pro- and anti-inflammatory factors, believed to be involved in the progression of diabetic polyneuropathy are associated with cardiovascular autonomic neuropathy, suggesting that these factors may also contribute to the pathogenesis of cardiovascular autonomic neuropathy. Our findings emphasize the importance of the neuro-immune regulatory system in the pathogenesis of neuropathy in type 1 diabetes.Trial registration: The study was approved by the North Denmark Regional Committee on Health Research Ethics (N2013-0077 and N2017-0045) and registered in public databases (Eudra CT 2013-004375-12 and clinicaltrials.gov NCT02138045.

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Section: Chemotactic Cytokines Are Not Associated With Cardiovascularsupporting

confidence: 84%

Circulating Inflammatory Markers are Inversely Associated with Heart Rate Variability Measures in type 1 Diabetes

Wegeberg

Okdahl

Fløyel

et al. 2020

Preprint

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“…As our group and others have reported, it is not common to find trans-protein quantitative trait loci (pQTLs) with large effect sizes and most trans-pQTLs occur in genes which encode receptors or that have other regulatory influences on the protein studied (46)(47)(48)(49)(50)(51). Thus, we hypothesize that one or more genes within the MS4A locus may be key modulators of sTREM2.…”

Section: Discussionmentioning

confidence: 78%

The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk

et al. 2019

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Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer’s disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer’s Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 × 10−15); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

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“…For example, variants located on 3p21.31 were significantly associated (rs145617407: β = 0.348, P = 2.58×10 -10 ) with plasma levels of macrophage inflammatory protein 1beta (MIP1b), a protein which is encoded by C-C motif chemokine ligand 4 (CCL4) located on 17q12 (50,54). The 3p21.31 locus contains genes which encode five members of the C-C motif chemokine receptor family (CCR1, CCR2, CCR3, CCR5, and CCR9) including a known receptor for CCL4 (CCR5) (55). Thus, we hypothesize that one or more genes within the MS4A locus are key regulators of sTREM2.…”

Section: Discussionmentioning

confidence: 99%

The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk

Deming¹,

Filipello²,

Cignarella³

et al. 2018

Preprint

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Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in the cerebrospinal fluid (CSF) have been associated with Alzheimer disease (AD) status. TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may help reveal biological mechanisms underlying AD and identify novel therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 levels. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with higher CSF sTREM2 levels (rs1582763; P = 1.15×10−15) and replicated in independent datasets. The variants associated with increased levels of sTREM2 are also associated with reduced AD risk and delayed age-at-onset. Rs1582763 influences expression of MS4A4A and MS4A6A in multiple tissues, suggesting that one or both of these genes are important for regulating sTREM2. MS4A genes encode transmembrane proteins that may play a role in intracellular protein trafficking in microglia. We used human macrophages to begin to test the relationship between MS4A4A and TREM2 and found that they co-localize intracellularly and that antibody-mediated targeting of MS4A4A reduces sTREM2. Thus, genetic, molecular, and cellular findings suggest that MS4A4A regulates sTREM2. These findings also provide a mechanistic explanation of the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 is involved in sporadic AD risk in general, not only in TREM2 risk-variant carriers.

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Emerging role of chemokine CC motif ligand 4 related mechanisms in diabetes mellitus and cardiovascular disease: friends or foes?

Cited by 82 publications

References 120 publications

Circulating Inflammatory Markers are Inversely Associated with Heart Rate Variability Measures in type 1 Diabetes

Circulating Inflammatory Markers are Inversely Associated with Heart Rate Variability Measures in type 1 Diabetes

The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk

The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk

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