Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis

Jager, Saskia C.A. de; Bermúdez, Beatriz; Bot, Ilze; Koenen, Rory R.; Bot, Martine; Kavelaars, Annemieke; Waard, Vivian de; Heijnen, Cobi J.; Muriana, Francisco J.G.; Weber, Christian; Berkel, Theo J.C. Van; Kuiper, Johan; Lee, Se Jin; Abia, Rocı́o; Biessen, Erik A. L.

doi:10.1084/jem.20100370

Cited by 174 publications

(159 citation statements)

References 30 publications

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“…These mediators contribute to a local inflammatory environment, which further activates resident fibroblasts, leading to a chronic wound-healing process and ultimately fibrosis (4). Indeed, it was previously demonstrated that GDF-15 acts as a macrophage recruitment signal through the CCR2/CCL2 axis (12). GDF-15 may thus be involved in immune recruitment to the lung at given stages by stimulating the release of mediators such as IL-6 and CCL2.…”

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confidence: 99%

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Growth Differentiation Factor 15, a Marker of Lung Involvement in Systemic Sclerosis, Is Involved in Fibrosis Development but Is not Indispensable for Fibrosis Development

Lambrecht

Smith

Wilde

et al. 2014

Arthritis & Rheumatology

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ObjectiveTransforming growth factor β superfamily members are involved in the pathogenesis of systemic sclerosis (SSc). Growth differentiation factor 15 (GDF‐15) is a distant member of this family. We undertook this study to evaluate the role of GDF‐15 in SSc pathogenesis.MethodsA longitudinal prospective cohort of SSc patients was screened for serum GDF‐15 levels using enzyme‐linked immunosorbent assay, and associations with clinical data were analyzed. In vitro stimulation experiments were performed on lung fibroblasts. The role of GDF‐15 in fibrosis development in vivo was evaluated in the bleomycin lung fibrosis model in GDF‐15–deficient mice.ResultsGDF‐15 was measured at baseline in serum samples from 119 SSc patients. An increase in GDF‐15 levels was observed in patients classified as having no skin involvement, those with limited cutaneous SSc, and those with diffuse cutaneous SSc. Moreover, baseline serum GDF‐15 levels correlated strongly with disease activity and extent of organ involvement, particularly clinical symptoms of lung fibrosis, including impact on lung function at prospective followup. This was mimicked in the bleomycin model of SSc, in which animals exposed to bleomycin had elevated expression levels of GDF‐15 in lung tissue. Lung fibroblasts isolated from GDF‐15–deficient mice showed reduced induction of interleukin‐6 and CCL2 upon bleomycin stimulation. Surprisingly, no differences in fibrosis development were observed between wild‐type and GDF‐15–deficient animals.ConclusionAn intriguing profile of serum GDF‐15 levels was found in SSc patients. GDF‐15 expression is induced during fibrosis development and markedly correlates with lung function impairment in this disease. The protein may participate in fibrosis initiation, but is not indispensable in the course of fibrosis development in vivo.

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confidence: 99%

“…From this perspective, elevated GDF-15 levels are considered an endogenous protective mechanism for limiting cardiovascular damage (11). GDF-15 expression is also involved in inflammation, as substantiated by its involvement in CCR2-mediated chemotaxis (12).…”

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confidence: 99%

Growth Differentiation Factor 15, a Marker of Lung Involvement in Systemic Sclerosis, Is Involved in Fibrosis Development but Is not Indispensable for Fibrosis Development

Lambrecht

Smith

Wilde

et al. 2014

Arthritis & Rheumatology

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“…Because extended upregulation of NAG-1 can be involved in the progress of human IBD, more careful evaluations of extended NAG-1 actions should be performed in the context of chronic inflammatory responses in IBD patients. For instance, increased NAG-1 expression can increase MCP-1 and its receptor expression in macrophages in a TGF-bRII-mediated pathway and promotes macrophage chemotaxis during chronic inflammation (18). Our recent investigations suggested also that NAG-1 can enhance the production of proinflammatory cytokines via activation of NF-kB, a central proinflammatory transcription factor, in the mucosal infection models (21,36).…”

Section: Discussionmentioning

confidence: 92%

“…Although NAG-1 is involved in acute stress-induced apoptotic process (10), increasing recent evidences demonstrated that NAG-1 can trigger homeostatic cellular responses and play protective roles in both physiological and pathological states, including chronic inflammation and tumorigenesis (16)(17)(18)(19). In response to the cytotoxic NSAIDs, cells also can produce the survival signals.…”

Section: Discussionmentioning

confidence: 99%

“…Although most intestinal epithelial cells maintain a low level of NAG-1 expression, apoptotic mucosal surface epithelial cells can have relatively high levels of NAG-1 (15). Although NAG-1 is involved in acute stress-induced apoptotic process (10), increasing recent evidences demonstrated that NAG-1 can trigger homeostatic cellular responses and play protective roles in both physiological and pathological states, including chronic inflammation and tumorigenesis (16)(17)(18)(19). NAG-1, one of the major secreted proteins induced by p53, is thought to be important for promoting p53-mediated activity associated with cell cycle arrest and apoptosis (20).…”

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confidence: 99%

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Early Epithelial Restitution by Nonsteroidal Anti-Inflammatory Drug–Activated Gene 1 Counteracts Intestinal Ulcerative Injuries

Choi

Hun

Park

et al. 2016

The Journal of Immunology

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In response to ulcerative mucosal injuries, intestinal epithelial restitution is a critical event in the early defense against harmful attacks by luminal Ags. Based on the assumption that epithelial NAG-1 is an endogenous regulator of ulcerative stress-induced injuries, the expression and functions of NAG-1 were investigated. Genetic ablation of NAG-1 decreased survival of mice with dextran sodium sulfate–induced intestinal ulcer and histologically delayed the epithelial restitution, confirming early protective roles of NAG-1 in ulcerative insults. Moreover, enhanced expression of NAG-1 during the wound-healing process was associated with epithelial cell migration and spreading. In response to ulcerative injury, RhoA GTPase, a cytoskeleton modulator, mediated epithelial restitution via enhanced motility. RhoA expression was prominently elevated in the restituting epithelia cells around the insulted wound bed and was attenuated by NAG-1 deficiency. Pharmacological intervention with RhoA thus attenuated NAG-1–mediated epithelial cell migration during epithelial restitution. Taken together, epithelial restitution was promoted by enhanced NAG-1 expression and subsequent enterocyte locomotion during the early wound-healing process, suggesting clinical usefulness of NAG-1 as a novel endogenous muco-protective factor or an indicator of therapeutic efficacy against the ulcerative gastrointestinal diseases, including inflammatory bowel disease.

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Raised circulating soluble growth differentiation factor 15 is negatively associated with testosterone level in hypogonadic men with type 2 diabetes

Mei

Lyu

et al. 2022

Diabetes Metabolism Res

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Aims Epidemiological studies consistently show that decreases in serum testosterone level are observed more frequently in men with type 2 diabetes mellitus (T2DM), while clinical investigations have demonstrated that an increased level of circulating growth differentiation factor‐15 (GDF‐15) are also related closely to T2DM. The aim of this study was to examine the potential relationship between serum GDF‐15 levels and hypogonadism in Chinese male patients with T2DM. Materials and Methods A total of 305 T2DM men were recruited between July 2020 and August 2021. GDF‐15 and total testosterone concentrations were quantified by an enzyme‐linked immunosorbent assay and LC/MS mass spectrometry, respectively. Multiple linear regression analysis, logistic regression, and restricted cubic splined models were used to examine the correlation between GDF‐15 levels and hypogonadism in these patients. Results When compared with T2DM patients without hypogonadism circulating GDF‐15 levels were significantly higher in the hypogonadism group [1081.83 (746.79,1539.94) versus 779.49 (548.46,1001.27), p < 0.001] and were associated positively with hypogonadism in unadjusted and fully adjusted multivariate regression models (p < 0.01). The fully adjusted regression coefficients with 95% confidence intervals for circulating GDF‐15 and testosterone deficiency were −1.795 (−2.929, −0.661). Serum GDF‐15 levels were also associated positively with testosterone deficiency in each logistic regression model (p < 0.05), while after adjustment for all risk factors, the same findings were obtained in the restricted cubic splined models (p < 0.01). Conclusions In hypogonadal men with T2DM, an elevated serum GDF‐15 level is associated negatively with serum testosterone concentration. GDF‐15 may be a novel cytokine related to T2DM men with hypogonadism.

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Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis

Abstract: The TGF-β family member GDF-15 promotes lesion formation and plaque instability in atherosclerosis-prone LDLr-deficient mice.

Cited by 174 publications

References 30 publications

Growth Differentiation Factor 15, a Marker of Lung Involvement in Systemic Sclerosis, Is Involved in Fibrosis Development but Is not Indispensable for Fibrosis Development

Growth Differentiation Factor 15, a Marker of Lung Involvement in Systemic Sclerosis, Is Involved in Fibrosis Development but Is not Indispensable for Fibrosis Development

Early Epithelial Restitution by Nonsteroidal Anti-Inflammatory Drug–Activated Gene 1 Counteracts Intestinal Ulcerative Injuries

Raised circulating soluble growth differentiation factor 15 is negatively associated with testosterone level in hypogonadic men with type 2 diabetes

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