Separating cytokine twins with a small molecule

Bernhagen, Jürgen

doi:10.1074/jbc.h119.011749

Cited by 3 publications

(4 citation statements)

References 10 publications

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“…Results from studies of Mif-2 -/-Apoe -/mice on a 24-week HFD treatment regimen are not available yet, but we would predict a similar protective phenotype for the Mif-2-deficient mice across the entire vascular bed. The protective effect of global Mif-2 gene deletion was confirmed in a pharmacological model, applying the MIF-2-selective small molecule inhibitor 4-CPPC (32,51). Consistently, similar results were obtained in 4-CPPC-injected Apoe -/mice after 4.5-week HFD.…”

Section: Discussionsupporting

confidence: 74%

“…To further confirm the role of MIF-2 in early atherogenesis and address the potential role of compensatory effects caused by global gene deficiency, we employed a pharmacological blockade approach, using 4-CPPC, a specific small molecule inhibitor of MIF-2 that exhibits a 13-fold selectivity against MIF-2 over MIF (32,51). Apoe -/mice were placed on a 4.5-week HFD and 4-CPPC versus vehicle control was administered in parallel to the HFD (intraperitoneal (i.p.)…”

Section: Genetic Deletion and Pharmacological Blockade Of Mif-2 Mitigate Atherosclerotic Lesion Formation In Early Stages Of Atheroscleromentioning

confidence: 99%

“…Despite its identification over 25 years ago, a role for D-DT in human immunity only emerged fairly recently, when D-DT was characterized as a cytokine and functional homolog of MIF (30). Accordingly, D-DT is now also termed MIF-2 (30)(31)(32). MIF-2 is expressed in numerous organs such as liver, heart, lung, and pancreas.…”

Section: Introductionmentioning

confidence: 99%

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MIF-2/D-DT is an atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

Bounkari

Zan

Wagner

et al. 2021

Preprint

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Atherosclerosis is the underlying cause of cardiovascular diseases (CVDs) such as myocardial infarction and ischemic stroke. It is a lipid-triggered chronic inflammatory condition of the arterial vascular wall that is driven by various inflammatory pathways including atherogenic cytokines and chemokines. D-dopachrome tautomerase (D-DT), also known as macrophage migration inhibitory factor-2 (MIF-2), belongs to the MIF protein family, which is best known for its pathogenic role in a variety of inflammatory and immune conditions including CVDs. While MIF is well known as a promoter of atherogenic processes, MIF-2 has not been studied in atherosclerosis. Here, we investigated atherosclerosis in hyperlipidemic Mif-2-/-Apoe-/- mice and studied the role of MIF-2 in various atherogenic assays in vitro. We found that global Mif-2 deficiency as well as its pharmacological blockade by 4-CPPC protected against atherosclerotic lesion formation and vascular inflammation in models of early and advanced atherogenesis. On cellular level, MIF-2 promoted monocyte migration in 2D and 3D and monocyte arrest on aortic endothelial monolayers, promoted B-cell chemotaxis in vitro and B-cell homing in vivo, and increased macrophage foam cell formation. Dose curves and direct comparison in a 3D migration set-up suggest that MIF-2 may be a more potent chemokine than MIF for monocytes and B cells. We identify CXCR4 as a novel receptor for MIF-2. The evidence relies on a CXCR4 inhibitor, CXCR4 internalization experiments, MIF-2/CXCR4 binding studies by yeast-CXCR4 transformants, and fluorescence spectroscopic titrations with a soluble CXCR4 surrogate. Of note, Mif-2-/- Apoe-/- mice exhibited decreased plasma cholesterol and triglyceride levels, lower body weights, smaller livers, and profoundly reduced hepatic lipid accumulation compared to Apoe-/- mice. Mechanistic experiments in Huh-7 hepatocytes suggest that MIF-2 regulates the expression and activation of sterol-regulatory element binding protein-1 and -2 (SREBP-1, SREBP-2) to induce lipogenic downstream genes such as FASN and LDLR, while it attenuated the activation of the SREBP inhibiting AMPK pathway. Studies using receptor Inhibitors showed that SREBP activation and hepatic lipoprotein uptake by MIF-2 is mediated by both CXCR4 and CD74. Lastly and in line with a combined role of MIF-2 in vascular inflammation and hepatic lipid accumulation, MIF-2 was found to be profoundly upregulated in unstable human carotid plaques, underscoring a critical role for MIF-2 in advanced stages of atherosclerosis. Together, these data identify MIF-2 as a novel atherogenic chemokine and CXCR4 ligand that not only promotes lesion formation and vascular inflammation but also strongly affects hepatic lipogenesis in an SREBP-mediated manner, possibly linking atherosclerosis and hepatic steatosis.

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Section: Discussionsupporting

confidence: 74%

Section: Genetic Deletion and Pharmacological Blockade Of Mif-2 Mitigate Atherosclerotic Lesion Formation In Early Stages Of Atheroscleromentioning

confidence: 99%

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MIF-2/D-DT is an atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

Bounkari

Zan

Wagner

et al. 2021

Preprint

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“…Despite its homologous action, other studies have revealed distinct or even inverse MIF-1/-2 action in cardiovascular disease, autoimmune disease, obesity, adipose tissue inflammation and wound healing [11,13,22,24,25]. More specifically, MIF-1 promotes while MIF-2 alleviates adipose tissue inflammation [11].…”

Section: Involvement Of the Macrophage Migration Inhibitory Factor (M...mentioning

confidence: 99%

Involvement of the Macrophage Migration Inhibitory Factor (MIF) in Lipedema

Vasella,

Wolf,

Francis

et al. 2023

Metabolites

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Lipedema is a chronic disorder that mainly affects women. It is often misdiagnosed, and its etiology remains unknown. Recent research indicates an accumulation of macrophages and a shift in macrophage polarization in lipedema. One known protein superfamily that contributes to macrophage accumulation and polarization is the macrophage migration inhibitory factor (MIF) family. MIF-1 and MIF-2 are ubiquitously expressed and also regulate inflammatory processes in adipose tissue. In this study, the expression of MIF-1, MIF-2 and CD74—a common receptor for both cytokines—was analyzed in tissue samples of 11 lipedema and 11 BMI-matched, age-matched and anatomically matched control patients using qPCR and immunohistochemistry (IHC). The mRNA expression of MIF-1 (mean 1.256; SD 0.303; p = 0.0485) and CD74 (mean 1.514; SD 0.397; p = 0.0097) were significantly elevated in lipedema patients, while MIF-2 expression was unaffected (mean 1.004; SD 0.358; p = 0.9718). The IHC analysis corroborated the results for CD74 expression on a cellular level. In conclusion, our results provide first evidence for a potential involvement of the MIF family, presumably via the MIF-1-CD74 axis, in lipedema.

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Targeted therapies and checkpoint inhibitors in sarcoma

Vasella

Gousopoulos

Guidi

et al. 2021

QJM: An International Journal of Medicine

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Sarcomas are defined as a group of mesenchymal malignancies with over 100 heterogeneous subtypes. As a rare and difficult to diagnose entity, micrometastasis is already present at the time of diagnosis in many cases. Current treatment practice of sarcomas consists mainly of surgery, (neo)adjuvant chemo- and/or radiotherapy. Although the past decade has shown that particular genetic abnormalities can promote the development of sarcomas, such as translocations, gain-of-function mutations, amplifications or tumor suppressor gene losses, these insights have not led to established alternative treatment strategies so far. Novel therapeutic concepts with immunotherapy at its forefront have experienced some remarkable success in different solid tumors while their impact in sarcoma remains limited. In this review, the most common immunotherapy strategies in sarcomas, such as immune checkpoint inhibitors, targeted therapy and cytokine therapy are concisely discussed. The programmed cell death (PD)-1/PD-1L axis and apoptosis-inducing cytokines, such as TNF-related apoptosis-inducing ligand (TRAIL), have not yielded the same success like in other solid tumors. However, in certain sarcoma subtypes, e.g. liposarcoma or undifferentiated pleomorphic sarcoma, encouraging results in some cases when employing immune checkpoint inhibitors in combination with other treatment options were found. Moreover, newer strategies such as the targeted therapy against the ancient cytokine macrophage migration inhibitory factor (MIF) may represent an interesting approach worth investigation in the future.

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Separating cytokine twins with a small molecule

Cited by 3 publications

References 10 publications

MIF-2/D-DT is an atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

MIF-2/D-DT is an atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

Involvement of the Macrophage Migration Inhibitory Factor (MIF) in Lipedema

Targeted therapies and checkpoint inhibitors in sarcoma

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