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Clearance of dying cells by efferocytosis is necessary for cardiac repair after myocardial infarction (MI). Recent reports have suggested a protective role for vascular endothelial growth factor C (VEGFC) during acute cardiac lymphangiogenesis after MI. Here, we report that defective efferocytosis by macrophages after experimental MI led to a reduction in cardiac lymphangiogenesis and Vegfc expression. Cell-intrinsic evidence for efferocytic induction of Vegfc was revealed after adding apoptotic cells to cultured primary macrophages, which subsequently triggered Vegfc transcription and VEGFC secretion. Similarly, cardiac macrophages elevated Vegfc expression levels after MI, and mice deficient for myeloid Vegfc exhibited impaired ventricular contractility, adverse tissue remodeling, and reduced lymphangiogenesis. These results were observed in mouse models of permanent coronary occlusion and clinically relevant ischemia and reperfusion. Interestingly, myeloid Vegfc deficiency also led to increases in acute infarct size, prior to the amplitude of the acute cardiac lymphangiogenesis response. RNA-Seq and cardiac flow cytometry revealed that myeloid Vegfc deficiency was also characterized by a defective inflammatory response, and macrophage-produced VEGFC was directly effective at suppressing proinflammatory macrophage activation. Taken together, our findings indicate that cardiac macrophages promote healing through the promotion of myocardial lymphangiogenesis and the suppression of inflammatory cytokines.

Once thought to be in a terminally differentiated state, macrophages are now understood to be highly pliable, attuned and receptive to environmental cues that control and align responses. In development of purpose, the centrality of metabolic pathways has emerged. Thus, macrophage inflammatory or reparative phenotypes are tightly linked to catabolic and anabolic metabolism, with further fine tuning of specific gene expression patterns in specific settings. Single-cell transcriptome analyses have revealed a breadth of macrophage signatures, with some new influencers driving phenotype. CD36/Scavenger Receptor B2 has established roles in immunity and lipid metabolism. Macrophage CD36 is a key functional player in metabolic expression profiles that determine phenotype. Emerging data show that alterations in the microenvironment can recast metabolic pathways and modulate macrophage function, with the potential to be leveraged for therapeutic means. This review covers recent data on phenotypic characterization of homeostatic, atherosclerotic, lipid-, tumor- and metastatic-associated macrophages, with the integral role of CD36 highlighted.

The trapping of lipid-laden macrophages in the arterial intima is a critical but reversible step in atherogenesis. However, the mechanism by which this occurs is not clearly defined. Here, we tested in mice the hypothesis that CD36, a class B scavenger receptor expressed on macrophages, has a role in this process. Using both in vivo and in vitro migration assays, we found that oxidized LDL (oxLDL), but not native LDL, inhibited migration of WT mouse macrophages but not CD36-deficient cells. We further observed a crucial role for CD36 in modulating the in vitro migratory response of human peripheral blood monocyte-derived macrophages to oxLDL. oxLDL also induced rapid spreading and actin polymerization in CD36-sufficient but not CD36-deficient mouse macrophages in vitro. The underlying mechanism was dependent on oxLDL-mediated CD36 signaling, which resulted in sustained activation of focal adhesion kinase (FAK) and inactivation of Src homology 2-containing phosphotyrosine phosphatase (SHP-2). The latter was due to NADPH oxidase-mediated ROS generation, resulting in oxidative inactivation of critical cysteine residues in the SHP-2-active site. Macrophage migration in the presence of oxLDL was restored by both antioxidants and NADPH oxidase inhibitors, which restored the dynamic activation of FAK. We conclude therefore that CD36 signaling in response to oxLDL alters cytoskeletal dynamics to enhance macrophage spreading, inhibiting migration. This may induce trapping of macrophages in the arterial intima and promote atherosclerosis.

Background White spot lesions (WSLs) are a formidable challenge during orthodontic treatment, affecting patients regardless of oral hygiene. Multifactorial in nature, amongst potential contributors to their development are the microbiome and salivary pH. The aim of our pilot study is to determine if pre-treatment differences in salivary Stephan curve kinetics and salivary microbiome features correlate with WSL development in orthodontic patients with fixed appliances. We hypothesize that non-oral hygiene determined differences in saliva could be predictive of WSL formation in this patient population through analysis of salivary Stephan curve kinetics, and that these differences would further manifest as changes in the oral microbiome. Methods In this prospective cohort study, twenty patients with initial simplified oral hygiene index scores of “good” that were planning to undergo orthodontic treatment with self-ligating fixed appliances for at least 12 months were enrolled. At pre-treatment stage, saliva was collected for microbiome analysis, and at 15-minute intervals after a sucrose rinse over 45 min for Stephan curve kinetics. Results 50% of patients developed a mean 5.7 (SEM: 1.2) WSLs. There were no differences in saliva microbiome species richness, Shannon alpha diversity or beta diversity between the groups. Capnocytophaga sputigena exclusively and Prevotella melaninogenica predominantly were found in WSL patients, while Streptococcus australis was negatively correlated with WSL development. Streptococcus mitis and Streptococcus anginosus were primarily present in healthy patients. There was no evidence to support the primary hypothesis. Conclusions While there were no differences in salivary pH or restitution kinetics following a sucrose challenge and no global microbial differences in WSL developers, our data showed change in salivary pH at 5 min associated with an abundance of acid-producing bacteria in saliva. The results suggest salivary pH modulation as a management strategy to inhibit the abundance of caries initiators. Our study may have uncovered the earliest predecessors to WSL/caries development.

The mechanism controlling long-chain fatty acid (LCFA) mobilization from adipose tissue is not well understood. Here, we investigated how the LCFA transporter CD36 regulates this process. By using tissue-specific KO mouse models, we showed that CD36 in adipocytes and endothelial cells mediated both LCFA deposition into and release from adipose tissue. We demonstrated the role of adipocytic and endothelial CD36 in promoting tumor growth and chemoresistance conferred by adipose tissue–derived LCFAs. We showed that dynamic cysteine S-acylation of CD36 in adipocytes, endothelial cells, and cancer cells mediated intercellular LCFA transport. We demonstrated that lipolysis induction in adipocytes triggered CD36 deacylation and deglycosylation, as well as its dissociation from interacting proteins, prohibitin-1 (PHB) and annexin 2 (ANX2). Our data indicate that lipolysis triggers caveolar endocytosis and translocation of CD36 from the cell membrane to lipid droplets. This study suggests a mechanism for both outside-in and inside-out cellular LCFA transport regulated by CD36 S-acylation and its interactions with PHB and ANX2.

Fatty acid translocase (CD36) is a scavenger receptor with multiple ligands and diverse physiological actions. We recently reported that alcohol-induced hepatic retinoid mobilization is impaired in Cd36 −/− mice, leading us to hypothesize that CD36 has a novel role in hepatic vitamin A mobilization. Given the central role of the liver in systemic vitamin A homeostasis we also postulated that absence of CD36 would affect whole-body vitamin A homeostasis. We tested this hypothesis in aging wild type and Cd36 −/− mice, as well as mice fed a vitamin A-deficient diet. In agreement with our hypothesis, Cd36 −/− mice accumulated hepatic retinyl ester stores with age to a greater extent than wild type mice. However, contrary to expectations, Cd36 −/− mice consuming a vitamin A-deficient diet mobilized hepatic retinoid similar to wild type mice. Interestingly, we observed that Cd36 −/− mice had significantly reduced white adipose tissue retinoid levels compared to wild type mice. In conclusion, we demonstrate that the absence of CD36 alters whole-body vitamin A homeostasis.

CD36 is a type 2 scavenger receptor with multiple functions. CD36 binding to oxidized LDL triggers signaling cascades that are required for macrophage foam cell formation, but the mechanisms by which CD36 signals remain incompletely understood. Mass spectrometry analysis of anti-CD36 immuno-precipitates from macrophages identified the tetraspanin CD9 as a CD36 interacting protein. Western blot showed that CD9 was precipitated from mouse macrophages by anti-CD36 monoclonal antibody and CD36 was likewise precipitated by anti-CD9, confirming the mass spectrometry results. Macrophages from cd36 null mice were used to demonstrate specificity. Membrane associations of the two proteins on intact cells was analyzed by confocal immunofluorescence microscopy and by a novel cross linking assay that detects proteins in close proximity (<40 nm). Functional significance was determined by assessing lipid accumulation, foam cell formation and JNK activation in wt, cd9 null and cd36 null macrophages exposed to oxLDL. OxLDL uptake, lipid accumulation, foam cell formation, and JNK phosphorylation were partially impaired in cd9 null macrophages. The present study demonstrates that CD9 associates with CD36 on the macrophage surface and may participate in macrophage signaling in response to oxidized LDL.

Background Sex differences in knee osteoarthritis (KOA) are well documented, but the molecular drivers within meniscal tissue remain unclear. We studied whether simulated microgravity (SMG) models sex‑dependent meniscal degeneration and whether the lipid scavenger receptor CD36 mediates these effects. Methods Human menisci from total knee arthroplasty (TKA) donors were analyzed (histology n  = 5 females/5 males; flow cytometry and RT‑qPCR n  = 7 females/7 males). In mice, we assessed spontaneous anterior‑horn mineralization by micro‑CT at 4, 12, and 24 weeks in wild‑type ( WT ) and CD36 ‑deficient ( Cd36 −/− ) animals. Four‑week menisci were then encapsulated in 1% agarose and cultured for 3 weeks under static or SMG conditions with serial micro‑CT (days 0, 7, 14, 21), histology, bulk RNA‑seq, and DIA shotgun proteomics. Results Female TKA menisci showed near‑complete glycosaminoglycan loss, disorganized type I collagen, and elevated hypertrophic markers ( COL10A1 , BMP2 , IHH ), with a trend toward more CD36 + cells. In vivo, a significant sex and genotype interaction emerged at 12 weeks in mouse model: Cd36 −/− females displayed ~ 15% less mineralization than WT. Ex vivo, SMG increased mineralization in WT females by ~ 25% at day 7 and ~ 30% at day 21 compared to static, but had minimal effect in males; Cd36 −/− females exhibited ~ 20–30% lower SMG‑induced mineralization than WT and preserved Safranin‑O and type II collagen. Transcriptomics under SMG revealed strong sex divergence: females showed enrichment of cell–matrix/mechanosignaling pathways, including ECM–receptor/focal‑adhesion and Ca/PI3K‑linked signaling, whereas males showed immune/osteoclast signatures. Proteomics paralleled these patterns: WT females under SMG had marked decreases in Col2a1 , Col11a1 , and Acan with increased oxidative‑phosphorylation proteins; Cd36 −/− females showed reduced abundance of mitochondrial respiratory proteins and vesicle/mineralization‑associated factors, consistent with reduced mineralization and preserved ECM. Conclusions SMG provides a controllable platform that recapitulates sex‑dependent, KOA‑like tissue degeneration. The data support a CD36-dependent mechanometabolic axis in females in which mechanical unloading disrupts ECM integrity, activates CD36-linked lipid handling with Ca/PI3K/AMPK signaling, and drives higher mitochondrial respiration and oxidative stress, culminating in ECM breakdown and mineralization, positioning CD36 as a promising sex-stratified therapeutic target in KOA.

Increased Hepatic CD36 Expression Contributes to Dyslipidemia Associated With Diet-Induced Obesity Debby P.Y. Koonen 1 , René L. Jacobs 2 , Maria Febbraio 3 , Martin E. Young 4 , Carrie-Lynn M. Soltys 1 , Huy Ong 5 , Dennis E. Vance 2 and Jason R.B. Dyck 1 1 Cardiovascular Research Group, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada 2 CIHR Group on the Molecular and Cellular Biology of Lipids, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada 3 Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 4 Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, Houston, Texas 5 Faculty of Pharmacy and Department of Pharmacology, Faculty of Medicine, Université de Montreal, Montreal, Quebec, Canada Address correspondence and reprint requests to Dr. Jason R.B. Dyck, 474 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2. E-mail: jason.dyck{at}ualberta.ca Abstract OBJECTIVE— The etiology of type 2 diabetes often involves diet-induced obesity (DIO), which is associated with elevated plasma fatty acids and lipoprotein associated triglycerides. Since aberrant hepatic fatty acid uptake may contribute to this, we investigated whether increased expression of a fatty acid transport protein (CD36) in the liver during DIO contributes to the dyslipidemia that precedes development of type 2 diabetes. RESEARCH DESIGN AND METHODS— We determined the effect DIO has on hepatic CD36 protein expression and the functional consequence of this in terms of hepatic triglyceride storage and secretion. In addition, in vivo adenoviral gene delivery of CD36 to the livers of lean mice was performed to determine if increased hepatic CD36 protein was sufficient to alter hepatic fatty acid uptake and triglyceride storage and secretion. RESULTS— During DIO, CD36 protein levels in the liver are significantly elevated, and these elevated levels correlate with increased hepatic triglyceride storage and secretion. These alterations in liver lipid storage and secretion were also observed upon forced expression of hepatic CD36 in the absence of DIO and were accompanied with a marked rise in hepatic fatty acid uptake in vivo, demonstrating that increased CD36 expression is sufficient to recapitulate the aberrant liver lipid handling observed in DIO. CONCLUSIONS— Increased expression of hepatic CD36 protein in response to DIO is sufficient to exacerbate hepatic triglyceride storage and secretion. As these CD36-mediated effects contribute to the dyslipidemia that often precedes the development of type 2 diabetes, increased hepatic CD36 expression likely plays a causative role in the pathogenesis of type 2 diabetes. ALT, alanine aminotransferase BMIPP, 15-p-[123I]iodophenyl-3-(R,S)-methyl pentadecanoic acid DIO, diet-induced obesity NEFA, nonesterified fatty acid SPECT, single photon emission computed tomography VLDL, very-low-density lipoprotein Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 29 August 2007. DOI: 10.2337/db07-0907. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted August 23, 2007. Received July 3, 2007. DIABETES