In this issue of the JCI, Vaisar et al. studied the proteome of HDL (see the related article beginning on page 746). They reveal, quite unexpectedly, that HDL is enriched in several proteins involved in the complement cascade, as well as in a variety of protease inhibitors, supporting the concept that HDL plays a role in innate immunity and in the regulation of proteolytic cascades involved in inflammatory and coagulation processes. The protein makeup of HDL also appears to be altered in patients with coronary artery disease. HDL proteomics is in its infancy, and preliminary findings will need to be confirmed using standardized approaches in larger clinical samples. However, this approach promises to better elucidate the relationship of HDL to atherosclerosis and its complications and could eventually help in the development of biomarkers to predict the outcome of interventions that alter HDL levels and functions.
Muredach P. Reilly, Alan R. Tall
The combination of the induction of lymphopenia and vaccination and/or T cell transfer is garnering much attention for cancer treatment. Preclinical studies have shown that the induction of lymphopenia by chemotherapy or radiation can enhance the antitumor efficacy of several distinct, cell-based immunotherapeutic approaches. The mechanism(s) by which such enhancement is achieved are being intensively studied, yet there is much opportunity for improvement. The animal studies reported by Wrzesinski and colleagues in this issue of the JCI are a promising and timely step in this direction (see the related article beginning on page 492). The authors have evaluated both the effect of increasing the intensity of lymphodepletion and the influence of HSC transfer on the in vivo function of adoptively transferred CD8+ T cells. We discuss their results in light of the evolving field and their implications for advancing cell-based immunotherapies for cancer.
Claudio Anasetti, James J. Mulé
It has become increasingly obvious that the notion of a terminally differentiated cell is likely a simplified concept. Epithelial-mesenchymal transition (EMT), during which epithelial cells assume a mesenchymal phenotype, is a key event occurring during normal development and pathological processes. Multiple extracellular stimuli and transcriptional regulators can trigger EMT, but how such distinct signaling pathways orchestrate the complex cellular events that facilitate EMT is not well understood. In this issue of the JCI, Venkov et al. report on their examination of fibroblasts resulting from EMT and describe a novel protein-DNA complex that is essential for transcription of fibroblast-specific protein 1 (FSP1) and sufficient to induce early EMT events (see the related article beginning on page 482). Collectively, their results suggest that this complex is an important regulator of the EMT transcriptome.
Yingqi Teng, Michael Zeisberg, Raghu Kalluri
The exact role(s) of the cytokine IFN-γ in the demyelinating disease multiple sclerosis remain controversial, with evidence suggesting both detrimental and protective effects of the cytokine in MS and MS models such as EAE. The study by Lin and coworkers in this issue of the JCI produces evidence that protective effects of IFN-γ on mature oligodendrocytes during EAE induction are mediated via activation of the pancreatic ER kinase (PERK), resulting in induction of the endoplasmic reticular stress response pathway (see the related article beginning on page 448). Modulation of this stress pathway has what we believe to be novel therapeutic potential for MS.
Jason R. Lees, Anne H. Cross
The way in which multiple cell types organize themselves into a carefully sculpted, 3D labyrinth of vessels that regulate blood flow throughout the body has been a longstanding mystery. Clinicians familiar with congenital cardiovascular disease recognize how genetic variants and modest perturbations in this complex set of spatiotemporal interactions and stochastic processes can result in life-threatening anomalies. Although the mystery is not yet fully solved, we are poised at an exciting juncture, as insights from murine disease models are converging with advances in human genetics to shed new light on puzzling clinical phenotypes of vascular disease. The study by High et al. in this issue of the JCI establishes a model system that mimics clinical features of congenital cardiovascular disease and further defines the role of the Notch signaling pathway in the neural crest as an essential determinant of cardiovascular structure (see the related article beginning on page 353).
Leonard M. Anderson, Gary H. Gibbons
Nutrient overload induces obesity, a primary risk factor for type 2 diabetes. Ribosomal biogenesis and protein synthesis, which are controlled by the mammalian target of rapamycin (mTOR), are primary energy-consuming processes in cells. mTOR phosphorylates and inactivates members of the eukaryotic translation initiation factor 4E–binding (eIF4E-binding) protein (4E-BP) family, which are translational repressors of 5′ cap–dependent protein synthesis. In this issue of the JCI, Le Bacquer et al. report that simultaneous deletion of both 4E-BP1 and 4E-BP2 in mice results in insulin resistance, decreased energy expenditure, and increased adipogenesis (see the related article beginning on page 387). These findings link protein synthesis, insulin sensitivity, and body weight.
HSCs are one of only a few cell types that resist HIV-1 infection despite the presence of HIV-1 receptors. An increasing number of genes have been identified that can reduce the sensitivity of cultured cells to retrovirus infection, and in this issue of the JCI, Zhang et al. identify p21Waf1/Cip1/Sdi1 (p21) as a gene product that can influence the sensitivity of HSCs to HIV-1 infection (see the related article beginning on page 473). Strikingly, p21 appears to alter the fate of nuclear HIV-1 DNA, promoting the formation of circular viral DNA forms rather than functional proviruses.
Paul D. Bieniasz
Drugs known as beta blockers, which antagonize the β-adrenergic receptor (β-AR), are an important component of the treatment regimen for chronic heart failure (HF). However, a significant body of evidence indicates that genetic heterogeneity at the level of the β1-AR may be a factor in explaining the variable responses of HF patients to beta blockade. In this issue of the JCI, Rochais et al. describe how a single amino acid change in β1-AR alters its structural conformation and improves its functional response to carvedilol, a beta blocker currently used in the treatment of HF (see the related article beginning on page 229). This may explain why some HF patients have better responses not only to carvedilol but to certain other beta blockers as well. The data greatly enhance our mechanistic understanding of myocardial adrenergic signaling and support the development of “tailored” or “personalized” medicine, in which specific therapies could be prescribed based on a patient’s genotype.
Brent R. DeGeorge, Walter J. Koch
Increased insulin secretion and expansion of pancreatic β cell mass work together to maintain normal glucose levels when insulin resistance develops. Changes in glucose concentration have long been known to have profound effects upon the rates of insulin secretion and β cell mass, but various other agents can also cause changes, raising questions about which mechanisms are dominant. Evidence favoring a dominant role for glucose is provided by Terauchi et al. in this issue of the JCI (see the related article beginning on page 246). Mice haploinsufficient for β cell glucokinase (Gck) were unable to increase their β cell mass in response to insulin resistance produced by high-fat feeding. Gck is known to be the glucose sensor for glucose metabolism in β cells. The study also provides strong evidence that insulin receptor substrate 2 (Irs2), which is known to have major effects on β cell growth and survival, is a key downstream mediator of the effects of glucose found in this study.
Gordon C. Weir, Susan Bonner-Weir
After intestinal injury, both the number and type of intestinal epithelial cells must be restored. Intestinal stem cells, located at the base of the intestinal crypt, repopulate the depleted crypt in a process known as compensatory proliferation. In this issue of the JCI, Brown et al. describe a new mechanism by which this process is regulated (see the related article beginning on page 258). Surprisingly, they find that a subset of stromal cells present within the intestinal tissue and expressing the proliferative factor prostaglandin-endoperoxidase synthase 2 (Ptgs2) is repositioned next to the intestinal stem cell compartment where local production of PGE2 controls injury-induced epithelial cell proliferation.
Seth Rakoff-Nahoum, Ruslan Medzhitov
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