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Toxic epidermal necrolysis (TEN) is an acute and life-threatening dermatological condition that is drug-induced and characterized by extensive epidermal detachment. These lesions should be protected from infection using a product that has a low risk of reactivity. Medical-grade honey (MGH) exerts antimicrobial and wound-healing effects while posing a low risk of exacerbating TEN. In this case report, we are the first to describe the use of MGH for wound management in two feline TEN patients. Case 1 involved a 1-year-old female British shorthair cat, while Case 2 featured a 1-year-old female mixed-breed cat. Both patients presented to the hospital with various symptoms, including fever, tongue lesions, and lesions in the abdominal area following ovariohysterectomy surgery. TEN was confirmed via histopathological examination. The suspected cause of TEN in both cases was the iodine present in the surgical scrub. Tongue lesions were addressed with a liquid diet, and all xenobiotics were immediately withdrawn as a precaution. MGH products supplemented with vitamins were applied to the abdominal wounds following a wound lavage with Ringer's lactate. Daily dressing changes were performed without discomfort, pain, or any adverse reactions. In both cases, debridement became evident after just 1 day, and the patients fully recovered after 12 days of MGH therapy. This case report demonstrates for the first time the successful use of supplemented MGH for wound management in veterinary patients with TEN. The patients did not have any adverse reactions to the treatment, while MGH dressings provided antimicrobial protection and wound-healing effects. Furthermore, these cases highlight the importance of rapid diagnosis and immediate drug withdrawal to increase the survival rate. Overall, supplemented MGH is a safe and effective method to treat TEN-related lesions in feline patients., Competing Interests: L.J.F.P and N.A.J.C. are employed by Triticum Exploitatie BV, Maastricht, the Netherlands. However, they were not involved in the design, treatment, and presentation of the results. The other author declares no conflicts of interest., (Copyright © 2024 Alexandra Peteoacă et al.)

Venous leg ulcers (VLUs) are hard-to-heal wounds and are prone to microbial colonization. Innovative and improved therapies are thus required to resolve local infection and enhance the wound healing process. The objective of this study was to evaluate the effectiveness of medical-grade honey (MGH) for the treatment of clinically infected and non-healing VLUs. This prospective case series included nine patients with an average age of 83.4 years (range: 75-91 years) with a total of eleven VLUs, previously ineffectively treated with various products. Major risk factors for the appearance of VLUs were chronic venous insufficiency, advanced age, multiple comorbidities (particularly cardiovascular diseases), and impaired mobility. All wounds presented with local signs of infection. Upon presentation, treatment was commenced with a range of MGH-based products (L-Mesitran ® ). Clinical signs of infection were eliminated by MGH after 2.2 weeks on average (range: 1-4 weeks), and wounds were completely healed after 7 weeks on average (range: 3-18 weeks). No further complications or recurrences were observed. MGH has a broad-spectrum antimicrobial activity and promotes rapid healing, thus improving patients' quality of life. Moreover, MGH-based products are safe, easy to use, cost-effective, and can effectively treat VLUs alone or in combination with standard-of-care therapies.

Introduction: Ageing of the global population has led to an increase in the demand for the treatment of wounds, especially considering the challenges of managing wounds in the elderly. Therefore, more effective treatment strategies need to be explored. In this article, we aimed to compare medical-grade honey (MGH) products with other wound care products and to provide guidelines on using MGH in wounds commonly found in the elderly., Methods: Based on literature research and expert opinion, an overview of commonly used wound care products and their wound healing characteristics is provided. In addition, literature-based classification of wounds in the elderly and the recommendations for treatments are provided., Results: Frequently used wound care products include povidone-iodine, enzymatic products, absorbing dressings, larvae, silver dressings, and MGH dressings. Supported by systematic reviews and meta-analyses, MGH dressings were identified as the most potent and all-round wound care product compared to the others. Next, we provided basic guidelines for managing the most common wounds in the elderly, both acute and chronic, and specified how and which MGH products can be used in these wounds., Conclusion: MGH is a widely applicable, safe, easy-to-use, and cost-effective product to manage wounds in the elderly. In case of doubt, refer to a trained wound care specialist who can support the treatment of difficult-to-heal wounds., Competing Interests: LJFP and NAJC are employed by Triticum Exploitatie BV, the manufacturer of L-Mesitran. Other authors state no conflict of interest., (© The Author(s) 2024.)

The prevalence of bacterial vaginosis (BV) among women of reproductive age is 29%. BV arises from a vaginal imbalance marked by reduced levels of lactic acid-producing lactobacilli and an overgrowth of pathogenic anaerobes. The multifactorial nature of BV's pathogenesis complicates its treatment. Current antibiotic therapy exhibits a recurrence rate of about 60% within a year. Recurrence can be caused by antibiotic treatment failure (e.g., due to antimicrobial resistance), the persistence of residual infections (e.g., due to biofilm formation), and re-infection. Because of the high recurrence rates, alternative therapies are required. Medical-grade honey (MGH), known for its antimicrobial and wound healing properties in wound care, emerges as a potential novel therapy for BV. MGH exerts broad-spectrum antimicrobial activity, employing multiple mechanisms to eliminate the risk of resistance. For example, the low pH of MGH and the production of hydrogen peroxide benefit the microbiota and helps restore the natural vaginal balance. This is supported by in vitro studies demonstrating that MGH has an antibacterial effect on several pathogenic bacteria involved in the pathophysiology of BV, while lactobacilli and the vaginal microenvironment can be positively affected. In contrast to antibiotics, MGH exerts anti-biofilm activity, affects the microbiome as pre- and probiotic, and modulates the vaginal microenvironment through its anti-inflammatory, anti-oxidative, physicochemical, and immunomodulatory properties. More clinical research is required to confirm the positive effect of MGH on BV and to investigate the long-term cure rate.

Burns are a major global healthcare concern, often complicated by the presence of bacteria such as Pseudomonas aeruginosa in the wounds. Silver-based dressings are commonly used in the treatment of burns but can cause skin irritation and delay healing time. Medical-grade honey (MGH) provides an interesting alternative. This study investigated the antimicrobial effects and possible cytotoxicity of L-Mesitran Soft (MGH-gel) and its individual components, Medihoney (Manuka), Flammazine (silver sulphadiazine), and silver nitrate (AgNO 3 ) in an ex vivo human burn wound model. Bacterial survival and wound healing parameters, including re-epithelialization and keratinocyte proliferation were assessed. L-Mesitran, Flammazine, and AgNO 3 reduced P. aeruginosa numbers below detection levels. L-Mesitran Soft exhibited a significantly stronger antimicrobial effect compared to Medihoney. The individual components of L-Mesitran contributed significantly to its antibacterial efficacy, thus suggesting synergistic activities. Moreover, L-Mesitran, Flammazine, and AgNO 3 slightly inhibited re-epithelialization while Medihoney treatment resulted in a complete lack of re-epithelialization and keratinocyte proliferation. Furthermore, clinical cases illustrated the effectiveness of MGH therapy in infected burns. Overall, L-Mesitran Soft had similar effects as silver-based products on bacterial load and epidermal regeneration, but outperformed Medihoney. Therefore, supplemented MGH could be used as an effective alternative to silver-based dressings for P. aeruginosa-infected burns., Competing Interests: Declaration of Competing Interest L.J.F.P and N.A.J.C. are employed by Triticum Exploitatie BV, Maastricht, the Netherlands. However, they were not involved in the design, treatment, and presentation of the results. All other authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

CCL17 is produced by conventional dendritic cells (cDCs), signals through CCR4 on regulatory T cells (Tregs), and drives atherosclerosis by suppressing Treg functions through yet undefined mechanisms. Here we show that cDCs from CCL17-deficient mice display a pro-tolerogenic phenotype and transcriptome that is not phenocopied in mice lacking its cognate receptor CCR4. In the plasma of CCL17-deficient mice, CCL3 was the only decreased cytokine/chemokine. We found that CCL17 signaled through CCR8 as an alternate high-affinity receptor, which induced CCL3 expression and suppressed Treg functions in the absence of CCR4. Genetic ablation of CCL3 and CCR8 in CD4 + T cells reduced CCL3 secretion, boosted FoxP3 + Treg numbers, and limited atherosclerosis. Conversely, CCL3 administration exacerbated atherosclerosis and restrained Treg differentiation. In symptomatic versus asymptomatic human carotid atheroma, CCL3 expression was increased, while FoxP3 expression was reduced. Together, we identified a non-canonical chemokine pathway whereby CCL17 interacts with CCR8 to yield a CCL3-dependent suppression of atheroprotective Tregs., Competing Interests: Competing Financial Interests The authors declare no competing financial interests.

Non-healing wounds are usually colonised and contaminated by different types of bacteria. An alternative to antibiotic treatment in patients with infected wounds with local signs of inflammation may be medical grade honey (MGH). MGH has antioxidant, antimicrobial, anti-inflammatory, and immunomodulatory features. This study aims to evaluate the effect of MGH therapy on infected non-healing wounds, especially for diabetic foot syndrome. Prospective, observational case series ( n = 5) of patients with wounds of diabetic foot syndrome are presented. There were five males with an average age of 61.6 years. All wounds were treated with MGH, and the healing trajectory was rigorously and objectively monitored. In all cases, there was a gradual disappearance of odour, pain, and exudation. Moreover, the wound areas significantly reduced within 40 days and there was a decrease in glycated haemoglobin and glycaemia values. All these outcomes resulted in improved quality of life of the patients. Despite bacterial colonisation, antibiotic treatment was not necessary. All wounds were completely healed. MGH has antimicrobial, anti-inflammatory, and antioxidant effects in diabetic foot syndrome wounds, does not increase glycated haemoglobin or glycaemia levels, and thus constitutes an effective alternative to the use of antibiotics in the treatment of locally infected wounds., Competing Interests: L.J.F.P. and N.A.J.C. are employed by Triticum Exploitatie BV, the manufacturer of the MGH-based product used in this study. However, they were not involved in the design of the study; the collection, analysis, or interpretation of the data; and the presentation of the results. They were solely consulted for their experience and expertise with MGH. All other authors declare no conflict of interest.

Introduction: The transmembrane protease A Disintegrin And Metalloproteinase 10 (ADAM10) displays a "pattern regulatory function," by cleaving a range of membrane-bound proteins. In endothelium, it regulates barrier function, leukocyte recruitment and angiogenesis. Previously, we showed that ADAM10 is expressed in human atherosclerotic plaques and associated with neovascularization. In this study, we aimed to determine the causal relevance of endothelial ADAM10 in murine atherosclerosis development in vivo ., Methods and Results: Endothelial Adam10 deficiency ( Adam10 ecko ) in Western-type diet (WTD) fed mice rendered atherogenic by adeno-associated virus-mediated PCSK9 overexpression showed markedly increased atherosclerotic lesion formation. Additionally, Adam10 deficiency was associated with an increased necrotic core and concomitant reduction in plaque macrophage content. Strikingly, while intraplaque hemorrhage and neovascularization are rarely observed in aortic roots of atherosclerotic mice after 12 weeks of WTD feeding, a majority of plaques in both brachiocephalic artery and aortic root of Adam10 ecko mice contained these features, suggestive of major plaque destabilization. In vitro , ADAM10 knockdown in human coronary artery endothelial cells (HCAECs) blunted the shedding of lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1) and increased endothelial inflammatory responses to oxLDL as witnessed by upregulated ICAM-1, VCAM-1, CCL5, and CXCL1 expression (which was diminished when LOX-1 was silenced) as well as activation of pro-inflammatory signaling pathways. LOX-1 shedding appeared also reduced in vivo , as soluble LOX-1 levels in plasma of Adam10 ecko mice was significantly reduced compared to wildtypes., Discussion: Collectively, these results demonstrate that endothelial ADAM10 is atheroprotective, most likely by limiting oxLDL-induced inflammation besides its known role in pathological neovascularization. Our findings create novel opportunities to develop therapeutics targeting atherosclerotic plaque progression and stability, but at the same time warrant caution when considering to use ADAM10 inhibitors for therapy in other diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van der Vorst, Maas, Theodorou, Peters, Jin, Rademakers, Gijbels, Rousch, Jansen, Weber, Lehrke, Lebherz, Yildiz, Ludwig, Bentzon, Biessen and Donners.)

Atherosclerosis is the foundation of potentially fatal cardiovascular diseases and it is characterized by plaque formation in large arteries. Current treatments aimed at reducing atherosclerotic risk factors still allow room for a large residual risk; therefore, novel therapeutic candidates targeting inflammation are needed. The endothelium is the starting point of vascular inflammation underlying atherosclerosis and we could previously demonstrate that the chemokine axis CXCL12-CXCR4 plays an important role in disease development. However, the role of ACKR3, the alternative and higher affinity receptor for CXCL12 remained to be elucidated. We studied the role of arterial ACKR3 in atherosclerosis using western diet-fed Apoe -/- mice lacking Ackr3 in arterial endothelial as well as smooth muscle cells. We show for the first time that arterial endothelial deficiency of ACKR3 attenuates atherosclerosis as a result of diminished arterial adhesion as well as invasion of immune cells. ACKR3 silencing in inflamed human coronary artery endothelial cells decreased adhesion molecule expression, establishing an initial human validation of ACKR3's role in endothelial adhesion. Concomitantly, ACKR3 silencing downregulated key mediators in the MAPK pathway, such as ERK1/2, as well as the phosphorylation of the NF-kB p65 subunit. Endothelial cells in atherosclerotic lesions also revealed decreased phospho-NF-kB p65 expression in ACKR3-deficient mice. Lack of smooth muscle cell-specific as well as hematopoietic ACKR3 did not impact atherosclerosis in mice. Collectively, our findings indicate that arterial endothelial ACKR3 fuels atherosclerosis by mediating endothelium-immune cell adhesion, most likely through inflammatory MAPK and NF-kB pathways., (© 2022. The Author(s).)

Platelets are key regulators of haemostasis, making platelet dysfunction a major driver of thrombosis. Numerous processes that determine platelet function are influenced by microRNAs (miRs). MiR-26b is one of the highest-expressed miRs in healthy platelets, and its expression in platelets is changed in a diseased state. However, the exact effect of this miR on platelet function has not been studied yet. In this study, we made use of a whole-body knockout of miR-26b in ApoE-deficient mice in order to determine its impact on platelet function, thrombus formation and platelet signalling both ex vivo and in vivo. We show that a whole-body deficiency of miR-26b exacerbated platelet adhesion and aggregation ex vivo. Additionally, in vivo, platelets adhered faster, and larger thrombi were formed in mice lacking miR-26b. Moreover, isolated platelets from miR-26b-deficient mice showed a hyperactivated Src and EGFR signalling. Taken together, we show here for the first time that miR-26b attenuates platelet adhesion and aggregation, possibly through Src and EGFR signalling.

Background:  Sunitinib is a multitarget tyrosine kinase inhibitor (TKI) used for cancer treatment. In platelets, sunitinib affects collagen-induced activation under noncoagulating conditions. We investigated (1) the effects of sunitinib on thrombus formation induced by other TK-dependent receptors, and (2) the effects under coagulating conditions. Cardiovascular disease is a comorbidity in cancer patients, resulting in possible aspirin treatment. Sunitinib and aspirin are associated with increased bleeding risk, and therefore we also investigated (3) the synergistic effects of these compounds on thrombus and fibrin formation., Methods:  Blood or isolated platelets from healthy volunteers or cancer patients were incubated with sunitinib and/or aspirin or vehicle. Platelet activation was determined by TK phosphorylation, flow cytometry, changes in [Ca 2+ ] i , aggregometry, and whole blood perfusion over multiple surfaces, including collagen with(out) tissue factor (TF) was performed., Results:  Sunitinib reduced thrombus formation and phosphatidylserine (PS) exposure under flow on collagen type I and III. Also, sunitinib inhibited glycoprotein VI-induced TK phosphorylation and Ca 2+ elevation. Upon TF-triggered coagulation, sunitinib decreased PS exposure and fibrin formation. In blood from cancer patients more pronounced effects of sunitinib were observed in lung and pancreatic as compared to neuroglioblastoma and other cancer types. Compared to sunitinib alone, sunitinib plus aspirin further reduced platelet aggregation, thrombus formation, and PS exposure on collagen under flow with(out) coagulation., Conclusion:  Sunitinib suppresses collagen-induced procoagulant activity and delays fibrin formation, which was aggravated by aspirin. Therefore, we urge for awareness of the combined antiplatelet effects of TKIs with aspirin, as this may result in increased risk of bleeding., Competing Interests: J.W.M.H. is a cofounder and shareholder of FlowChamber B.V. The other authors declare no relevant conflicts of interest., (Thieme. All rights reserved.)

Proprotein convertase subtilin/kexin type 9 (PCSK9) is a protease secreted mainly by hepatocytes and in lesser quantities by intestines, pancreas, and vascular cells. Over the years, this protease has gained importance in the field of cardiovascular biology due to its regulatory action on the low-density lipoprotein receptor (LDLR). However, recently, it has also been shown that PCSK9 acts independent of LDLR to cause vascular inflammation and increase the severity of several cardiovascular disorders. We hypothesized that PCSK9 affects the expression of chemokine receptors, major mediators of inflammation, to influence cardiovascular health. However, using overexpression of PCSK9 in murine models in vivo and PCSK9 stimulation of myeloid and vascular cells in vitro did not reveal influences of PCSK9 on the expression of certain chemokine receptors that are known to be involved in the development and progression of atherosclerosis and vascular inflammation. Hence, we conclude that the inflammatory effects of PCSK9 are not associated with the here investigated chemokine receptors and additional research is required to elucidate which mechanisms mediate PCSK9 effects independent of LDLR.

Atherosclerosis is the main underlying cause of cardiovascular diseases (CVDs), which remain the number one contributor to mortality worldwide. Although current therapies can slow down disease progression, no treatment is available that can fully cure or reverse atherosclerosis. Nanomedicine, which is the application of nanotechnology in medicine, is an emerging field in the treatment of many pathologies, including CVDs. It enables the production of drugs that interact with cellular receptors, and allows for controlling cellular processes after entering these cells. Nanomedicine aims to repair, control and monitor biological and physiological systems via nanoparticles (NPs), which have been shown to be efficient drug carriers. In this review we will, after a general introduction, highlight the advantages and limitations of the use of such nano-based medicine, the potential applications and targeting strategies via NPs. For example, we will provide a detailed discussion on NPs that can target relevant cellular receptors, such as integrins, or cellular processes related to atherogenesis, such as vascular smooth muscle cell proliferation. Furthermore, we will underline the (ongoing) clinical trials focusing on NPs in CVDs, which might bring new insights into this research field.

Background: MicroRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. One of the miRNAs that has been shown to play a role in various pathologies like cancer, neurological disorders and cardiovascular diseases is miRNA-26b. However, these studies only demonstrated rather ambiguous associations without revealing a causal relationship. Therefore, the aim of this study is to establish and validate a mouse model which enables the elucidation of the exact role of miRNA-26b in various pathologies., Results: A miRNA-26b-deficient mouse model was established using homologous recombination and validated using PCR. miRNA-26b-deficient mice did not show any physiological abnormalities and no effects on systemic lipid levels, blood parameters or tissue leukocytes. Using next generation sequencing, the gene expression patterns in miRNA-26b-deficient mice were analyzed and compared to wild type controls. This supported the already suggested role of miRNA-26b in cancer and neurological processes, but also revealed novel associations of miRNA-26b with thermogenesis and allergic reactions. In addition, detailed analysis identified several genes that seem to be highly regulated by miRNA-26b, which are linked to the same pathological conditions, further confirming the role of miRNA-26b in these pathologies and providing a strong validation of our mouse model., Conclusions: miRNA-26b plays an important role in various pathologies, although causal relationships still have to be established. The described mouse model of miRNA-26b deficiency is a crucial first step towards the identification of the exact role of miRNA-26b in various diseases that could identify miRNA-26b as a promising novel diagnostic or even therapeutic target in a broad range of pathologies.

The calcium sensing receptor (CaSR) is a G-protein coupled receptor that especially plays an important role in the sensing of extracellular calcium to maintain its homeostasis. Several in-vitro studies demonstrated that CaSR plays a role in adipose tissue metabolism and inflammation, resulting in systemic inflammation and contributing to atherosclerosis development. The aim of this study was to investigate whether adipocyte CaSR plays a role in adipose tissue inflammation in-vivo and atherosclerosis development. By using a newly established conditional mature adipocyte specific CaSR deficient mouse on a hyperlipidemic and atherosclerosis prone Apoe -/- background it could be shown that CaSR deficiency in adipocytes does neither contribute to initiation nor to progression of atherosclerotic plaques as judged by the unchanged lesion size or composition. Additionally, CaSR deficiency did not influence gonadal visceral adipose tissue (vAT) inflammation in-vivo, although a small decrease in gonadal visceral adipose cholesterol content could be observed. In conclusion, adipocyte CaSR seems not to be involved in vAT inflammation in-vivo and does not influence atherosclerosis development in hyperlipidemic Apoe -/- mice.

Dysfunctional adipose tissue (AT) may contribute to the pathology of several metabolic diseases through altered lipid metabolism, insulin resistance, and inflammation. Atypical chemokine receptor 3 (ACKR3) expression was shown to increase in AT during obesity, and its ubiquitous elimination caused hyperlipidemia in mice. Although these findings point towards a role of ACKR3 in the regulation of lipid levels, the role of adipocyte-specific ACKR3 has not yet been studied exclusively in this context. In this study, we established adipocyte- and hepatocyte-specific knockouts of Ackr3 in ApoE-deficient mice in order to determine its impact on lipid levels under hyperlipidemic conditions. We show for the first time that adipocyte-specific deletion of Ackr3 results in reduced AT triglyceride and cholesterol content in ApoE-deficient mice, which coincides with increased peroxisome proliferator-activated receptor-γ (PPAR-γ) and increased Angptl4 expression. The role of adipocyte ACKR3 in lipid handling seems to be tissue-specific as hepatocyte ACKR3 deficiency did not demonstrate comparable effects. In summary, adipocyte-specific ACKR3 seems to regulate AT lipid levels in hyperlipidemic Apoe -/- mice, which may therefore be a significant determinant of AT health. Further studies are needed to explore the potential systemic or metabolic effects that adipocyte ACKR3 might have in associated disease models.

There are still major challenges regarding the early diagnosis and treatment of chronic kidney disease (CKD), which is in part due to the fact that its pathophysiology is very complex and not clarified in detail. The diagnosis of CKD commonly is made after kidney damage has occurred. This highlights the need for better mechanistic insight into CKD as well as improved clinical tools for both diagnosis and treatment. In the last decade, many studies have focused on microRNAs (miRs) as novel diagnostic tools or clinical targets. MiRs are small non-coding RNA molecules that are involved in post-transcriptional gene regulation and many have been studied in CKD. A wide array of pre-clinical and clinical studies have highlighted the potential role for miRs in the pathogenesis of hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, kidney tubulointerstitial fibrosis, and some of the associated cardiovascular complications. In this review, we will provide an overview of the miRs studied in CKD, especially highlighting miR-103a-3p, miR-192-5p, the miR-29 family and miR-21-5p as these have the greatest potential to result in novel therapeutic and diagnostic strategies.

MicroRNAs (miRNAs) are short sequences of non-coding RNA that play an important role in the regulation of gene expression and thereby in many physiological and pathological processes. Furthermore, miRNAs are released in the extracellular space, for example in vesicles, and are detectable in various biological fluids, such as serum, plasma, and urine. Over the last years, it has been shown that miRNAs are crucial in the development of several cardiovascular diseases (CVDs). This review discusses the (patho)physiological implications of miRNAs in CVD, ranging from cardiovascular risk factors (i.e., hypertension, diabetes, dyslipidemia), to atherosclerosis, myocardial infarction, and cardiac remodeling. Moreover, the intriguing possibility of their use as disease-specific diagnostic and prognostic biomarkers for human CVDs will be discussed in detail. Finally, as several approaches have been developed to alter miRNA expression and function (i.e., mimics, antagomirs, and target-site blockers), we will highlight the miRNAs with the most promising therapeutic potential that may represent suitable candidates for therapeutic intervention in future translational studies and ultimately in clinical trials. All in all, this review gives a comprehensive overview of the most relevant miRNAs in CVD and discusses their potential use as biomarkers and even therapeutic targets., (Copyright © 2020 Peters, Biessen, Hohl, Weber, van der Vorst and Santovito.)

Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVDs), is a lipid-driven, inflammatory disease of the large arteries. Gold standard therapy with statins and the more recently developed proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have improved health conditions among CVD patients by lowering low density lipoprotein (LDL) cholesterol. Nevertheless, a substantial part of these patients is still suffering and it seems that 'just' lipid lowering is insufficient. The results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) have now proven that inflammation is a key driver of atherosclerosis and that targeting inflammation improves CVD outcomes. Therefore, the identification of novel drug targets and development of novel therapeutics that block atherosclerosis-specific inflammatory pathways have to be promoted. The inflammatory processes in atherosclerosis are facilitated by a network of immune cells and their subsequent responses. Cell networking is orchestrated by various (inflammatory) mediators which interact, bind and induce signaling. Over the last years, G-protein coupled receptors (GPCRs) emerged as important players in recognizing these mediators, because of their diverse functions in steady state but also and specifically during chronic inflammatory processes - such as atherosclerosis. In this review, we will therefore highlight a selection of these receptors or receptor sub-families mainly expressed on myeloid cells and their role in atherosclerosis. More specifically, we will focus on chemokine receptors, both classical and atypical, formyl-peptide receptors, the chemerin receptor 23 and the calcium-sensing receptor. When information is available, we will also describe the consequences of their targeting which may hold promising options for future treatment of CVD.

Objective- Expression of the chemokine-like receptor ChemR23 (chemerin receptor 23) has been specifically attributed to plasmacytoid dendritic cells (pDCs) and macrophages and ChemR23 has been suggested to mediate an inflammatory immune response in these cells. Because chemokine receptors are important in perpetuating chronic inflammation, we aimed to establish the role of ChemR23-deficiency on macrophages and pDCs in atherosclerosis. Approach and Results- ChemR23-knockout/knockin mice expressing eGFP (enhanced green fluorescent protein) were generated and after crossing with apolipoprotein E-deficient ( Apoe -/- ChemR23 e/e ) animals were fed a western-type diet for 4 and 12 weeks. Apoe -/- ChemR23 e/e mice displayed reduced lesion formation and reduced leukocyte adhesion to the vessel wall after 4 weeks, as well as diminished plaque growth, a decreased number of lesional macrophages with an increased proportion of M2 cells and a less inflammatory lesion composition after 12 weeks of western-type diet feeding. Hematopoietic ChemR23-deficiency similarly reduced atherosclerosis. Additional experiments revealed that ChemR23-deficiency induces an alternatively activated macrophage phenotype, an increased cholesterol efflux and a systemic reduction in pDC frequencies. Consequently, expression of the pDC marker SiglecH in atherosclerotic plaques of Apoe -/- ChemR23 e/e mice was declined. ChemR23-knockout pDCs also exhibited a reduced migratory capacity and decreased CCR (CC-type chemokine receptor)7 expression. Finally, adoptive transfer of sorted wild-type and knockout pDCs into Apoe -/- recipient mice revealed reduced accumulation of ChemR23-deficient pDCs in atherosclerotic lesions. Conclusions- Hematopoietic ChemR23-deficiency increases the proportion of alternatively activated M2 macrophages in atherosclerotic lesions and attenuates pDC homing to lymphatic organs and recruitment to atherosclerotic lesions, which synergistically restricts atherosclerotic plaque formation and progression.