EDITOR'S PICK: New insight into childhood metabolic disease
Glutaric acidemia type I (GA-I) is an inherited disorder similar to Huntington disease. Individuals with GA-I are unable to breakdown completely the amino acids lysine and tryptophan and the intermediates of lysine and tryptophan breakdown accumulate in the brain. In most, but not all, affected children, a period of normal development is followed by an irreversible brain injury triggered by a nonspecific illness. If children with GA-I reach 5 years of age without suffering brain injury they usually never show symptoms of the disease. New research using a mouse model of GA-I (Gcdh–/– mice) by William Zinnanti and colleagues at Penn State, Hershey, has provided insight into the mechanisms underlying injury and age-dependent susceptibility to the disease and suggested a way to monitor children with the disease.
Gcdh–/– mice do not develop disease if lysine and tryptophan are excluded from their diet. Exposure to lysine in the diet caused brain damage in both young and adult mice, but the extent of the damage was much greater in the young mice. This was shown to be because lysine uptake is enhanced in the immature brain compared with the adult brain and so more intermediates of lysine degradation accumulated, thereby increasing the susceptibility to brain damage. Treating young Gcdh–/– mice with homoarginine, to limit brain uptake of lysine, and glucose, to limit lysine degradation, substantially decreased brain damage caused by exposure to lysine in the diet. Furthermore, brain injury was preceded by decreases in glutamate and GABA in the brain that could be monitored by proton nuclear magnetic resonance spectroscopy, providing hope that a way of monitoring children with GA-I to predict the onset of brain injury might be developed.
TITLE: Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I
AUTHOR CONTACT:
William J. Zinnanti
Penn State College of Medicine, Hershey, Pennsylvania, USA.
Phone: (717) 531-5635; Fax: (717) 531-5634; E-mail: wjz105@psu.edu.
Keith C. Cheng
Penn State College of Medicine, Hershey, Pennsylvania, USA.
Phone: (717) 531-5635; Fax: (717) 531-5634; E-mail: kcheng76@gmail.com.
MEDIA CONTACT:
Megan Manlove
Penn State College of Medicine, Hershey, Pennsylvania, USA.
E-mail: mmanlove@hmc.psu.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31617
CARDIOLOGY: Mast cells get straight As
Abdominal aortic aneurysm (AAA) is a common disease of the main artery (the aorta) in the elderly. It is characterized by a dilated aorta and if allowed to develop unchecked it can rupture, an event with a high rate of mortality. In a new study, Guo-Ping Shi and colleagues at, Harvard Medical School, Boston, have demonstrated a role for immune cells known as mast cells in the development of disease in a mouse model of AAA.
Mast cells were shown to accumulate in AAA lesions in mice and mice lacking mast cells failed to develop AAA lesions. AAA lesion development could be restored in mast cell–deficient mice by reconstituting the mice with normal mast cells but not mast cells lacking either IL-6 or IFN-gamma. The authors therefore suggest that mast cells participate in AAA by releasing the pro-inflammatory cytokines IL-6 and IFN-gamma, which induce the degradation of extracellular matrix in the wall of the aorta and the death of smooth muscle cells in the wall of the aorta, events that weaken the wall of the aorta, allowing it to dilate. Preventing mast cell release of cytokines and proteases might therefore provide a new approach to controlling AAA in humans.
TITLE: Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice
AUTHOR CONTACT:
Guo-Ping Shi
Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 525-4358; Fax: 617) 525-4380; E-mail: gshi@rics.bwh.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31311
ONCOLOGY: CD8+ T cells LAG behind
New data generated using mice by Charles Drake and colleagues at Johns Hopkins University School of Medicine, Baltimore, have identified a role for the protein LAG-3 in limiting the response of immune cells known as CD8+ T cells to both host and tumor proteins. The authors therefore suggest that blocking LAG-3 might provide a new adjunct approach to treating individuals with cancer.
High levels of LAG-3 were shown to be expressed by CD8+ T cells after they had been activated. Analysis of the immune response to proteins engineered to be expressed by either normal tissue or tumor tissue revealed that blocking LAG-3 increased the reactivity of CD8+ T cells specific for these proteins. Furthermore, when combined with a cancer vaccine, LAG-3 blockade enhanced the specific immune response to a tumor, resulting in decreased tumor progression. The authors therefore suggest that it might be possible to improve the effectiveness of cancer vaccines currently under development by combining them with a therapeutic that blocks LAG-3 function on CD8+ T cells.
TITLE: LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems
AUTHOR CONTACT:
Charles G. Drake
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Phone: (410) 502-7523; Fax: (410) 614-0549; E-mail: drakech@jhmi.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31184
METABOLIC DISEASE: It’s good to talk: PGC-1-alpha helps skeletal muscle and pancreatic islets communicate
Some individuals with type 2 diabetes (which is characterized by abnormally high blood glucose levels) have lower than normal amounts of the protein PGC-1-alpha in their skeletal muscles, but it is not known whether this has a role in the onset of diabetes or if it is caused by the diabetes. Using mice that lack PGC-1-alpha in their skeletal muscle (MKO mice), Bruce Spiegelman and colleagues from the Dana-Farber Cancer Institute, Boston, have now shown that decreased expression of PGC-1-alpha can cause dysregulation of blood glucose levels.
When fed either a normal or high-fat diet MKO mice had much higher blood glucose levels than wild-type mice. This was because the beta-cells of the pancreas secreted less insulin, the hormone that prevents blood glucose levels from soaring. Higher levels of the soluble factor IL-6 were also detected in the blood. As IL-6 treatment decreased insulin secretion by wild-type and MKO pancreatic islets, the authors suggested that PGC-1-alpha mediates crosstalk between skeletal muscle and pancreatic islets through IL-6.
TITLE: Abnormal glucose homeostasis in skeletal muscle–specific PGC-1-alpha knockout mice reveals skeletal muscle–pancreatic beta-cell crosstalk
AUTHOR CONTACT:
Bruce M. Spiegelman
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Phone: (617) 632-3567; Fax: (617) 632-4655; E-mail: bruce_spiegelman@dfci.harvard.edu.
MEDIA CONTACT:
William Schaller
Media Office
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
E-mail: william_schaller@dfci.harvard.edu.
Beat Mueller
Communications Department
University of Zurich, Zurich, Switzerland.
E-mail: beat.mueller@unicom.uzh.ch.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31785
HEMATOLOGY: HRI controls anemia of inflammation with an iron fist
Maintaining the appropriate amount of iron in our bodies is important, too little results in anemia and too much is also toxic to the body. Anemia is a symptom of many different diseases including erythroid protoporphyria and beta-thalassemia. It is also observed in individuals who suffer from chronic diseases such as autoimmune diseases and cancer when it is known as anemia of inflammation. The protein HRI has been shown to have a role in anemia in individuals with erythroid protoporphyria and beta-thalassemia and new research using HRI-deficient mice by Jan-Jane Chen and colleagues at Massachusetts Institute of Technology, Cambridge, has now suggested a role for this protein in the anemia of inflammation.
When stimulated with LPS, HRI-deficient mice showed impaired maturation of immune cells known as macrophages and mounted an impaired anti-inflammatory response. This was associated with decreased production of hepcidin, a protein that controls iron levels by inhibiting the absorption of dietary iron from the intestine and the release of iron from senescent red blood cells by macrophages. These data indicate that HRI deficiency attenuates hepcidin expression and suggest a role for HRI in the anemia of inflammation.
TITLE: The function of heme-regulated eIF2-alpha kinase in murine iron homeostasis and macrophage maturation
AUTHOR CONTACT:
Jane-Jane Chen
Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Phone: (617) 253-9674; Fax: (617) 253-3459; E-mail: j-jchen@mit.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32084
INFLAMMATION: Interrupting interactions might benefit individuals who are arthritic
Rheumatoid arthritis (RA) is a chronic inflammatory disease one characteristic of which is the deposition of the protein fibrin in the joints, where it forms a matrix that contributes to the loss of joint mobility and function. In a new study, Jay Degen and colleagues from Cincinnati Children’s Hospital Research Foundation, Cincinnati, have shown that in mouse models of inflammatory joint disease fibrin and its precursor fibrinogen are factors that contribute to the development of disease.
Mice lacking fibrinogen or expressing a mutant form of fibrinogen that is unable to bind the integrin alpha-M-beta-2 developed less severe joint disease than normal mice when administered collagen (the collagen-induced arthritis model of RA). Inflammatory cells still accumulated in the joints, but these cells produced less of the proinflammatory cytokines TNF-alpha, IL-1-beta, and IL-6. Consistent with a role for fibrinogen and fibrin upstream of proinflammatory cytokine production, joint disease induced by overexpression of TNF-alpha was not attenuated in mice lacking fibrinogen. The authors therefore suggest that blocking the interaction between fibrinogen and alpha-M-beta-2 might provide a new approach to treating individuals with arthritic disease.
TITLE: Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alpha-M-beta-2 binding motif
AUTHOR CONTACT:
Jay L. Degen
Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio, USA.
Phone: (513) 636-4679; Fax: (513) 636-4317; E-mail: degenjl@cchmc.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30134
IMMUNOLOGY: The ins and outs of how neutrophils combat microbes
Immune cells known as neutrophils produce reactive oxygen intermediates (ROIs) to combat infection with microbes that can cause diseases such as pneumonia. New insight into the molecular pathway regulating neutrophil production of ROIs in mice has been provided by Wojciech Swat and colleagues at Washington University School of Medicine, St. Louis.
Several signals are needed to stimulate neutrophils to produce ROIs , including signals generated by neutrophils adhering to the extracellular matrix. In this study, the proteins Vav and PLC-gamma-2 were shown to be essential for neutrophil production of ROIs in response to various adhesion-dependent stimuli. They were found to be part of a signaling pathway that linked integrin-mediated adhesion to the NADPH oxidase complex that produces ROIs. Importantly, mice lacking Vav were unable to control infection with either Pseudomonas aeruginosa or Staphylococcus aureus, 2 common microbes associated with fatal cases of hospital-acquired pneumonia.
TITLE: Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLC-gamma-2 signaling axis in mice
AUTHOR CONTACT:
Wojciech Swat
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32729
ONCOLOGY: Understanding how the molecule RHPS4 targets tumor cells
New data generated by Annamaria Biroccio and colleagues at the Regina Elena National Cancer Institute, Rome, have provided a molecular characterization of the anticancer effects of the molecule RHPS4.
RHPS4 was shown to trigger a rapid and potent ATR-mediated DNA damage response at telomeres in vitro in human transformed fibroblasts and melanoma cells. When administered to mice transplanted with human tumor cells, RHPS4 induced telomere damage to the human tumor cells that resulted in tumor cell death by a process known as apoptosis. However, if the human tumor cells had been engineered to overexpress the telomere-protective factors TRF2 and POT1 RHPS4 had no anticancer effect. The authors therefore suggest that targeting telomeres, TRF2, or POT1 might provide new approaches to treating individuals with cancer.
TITLE: Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect
AUTHOR CONTACT:
Annamaria Biroccio
Regina Elena National Cancer Institute, Rome, Italy.
Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32461
Journal
Journal of Clinical Investigation