JCI early table of contents for Feb. 24, 2014

(Press-News.org) PPAR-γ agonist reverses cigarette smoke induced emphysema in mice Pulmonary emphysema results in irreversible lung damage and is most often the result of long term cigarette smoke exposure. Immune cells, such as macrophages and myeloid dendritic cells (mDCs) accumulate in the lungs of smokers with emphysema and release cytokines associated with autoimmune and inflammatory responses. In this issue of the Journal of Clinical Investigation Farrah Kheradmand and colleagues at Baylor University found that peroxisome proliferator activated receptor-γ (PPARγ) is downregulated in mDCs isolated from the lungs of emphysema patients and mice exposed to chronic cigarette smoke. Mice with PPARγ-deficient mDCs exhibited spontaneous lung inflammation and emphysema; moreover, treatment of smoke-exposed mice with a PPARγ agonist reversed emphysema development despite continuous exposure to cigarette smoke. In the accompanying commentary, Neil Kelly and Steven Shapiro of the University of Pennsylvania discuss the potential of PPARγ agonists to restore lung capacity in emphysema patients. TITLE: Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema AUTHOR CONTACT: Farrah Kheradmand
Baylor College of Medicine, Houston, TX , USA
Phone: 713 798 8622; Fax: 713 798 2050; E-mail: farrahk@bcm.edu View this article at: http://www.jci.org/articles/view/70587?key=fcd167331305da14dc27 ACCOMPANYING COMMENTARY TITLE: PPARγ in emphysema: blunts the damage and triggers repair? AUTHOR CONTACT: Steven D. Shapiro
University of Pittsburgh, Pittsburgh, PA, USA
Phone: 412-648-9641; Fax: 412-648-2117; E-mail: shapirosd@upmc.edu View this article at: http://www.jci.org/articles/view/74417?key=10b257ee4b8cf9c4efca Small molecule-dependent redcution of glutamate improves murine ALS Dysfunctional regulation of the excitatory neurotransmitter glutamate can lead to excitotoxicity and neurodegeneration. The excitatory amino acid transporter 2 (EAAT2), which is responsible for glutamate uptake is frequently reduced in patients with neurodegenerative diseases such as Alzheimer's disease and ALS. In this issue of the Journal of Clinical Investigation, Chien-Liang Glenn Lin and colleagues at the Ohio State University used a murine model of ALS to examine the ability of a drug compound (LDN/OSU-0212320) to enhance expression of EAAT2 and reduce levels of synaptic glutamate. They found that this compound increased EAAT2 expression and protected cultured neurons from exocitotoxic injury and death. Furthermore, LDN/OSU-0212320 treatment delayed the onset of neurodegenerative-associated declines in motor function and extended lifespan ALS mice. In the accompanying commentary, Allison Limpert and Nicholas Cosford of the Sanford Burnham Institute for Medical Research discus the potential benefits of EEAT2 modulation in treating neurodegenerative disease. TITLE: Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection AUTHOR CONTACT: Chien-liang Lin
The Ohio State University, Columbus, OH, USA
Phone: 614-688-5433; E-mail: lin.492@osu.edu View this article at: http://www.jci.org/articles/view/66163?key=e1e83af15e523f8bfd32 ACCOMPANYING COMMENTARY TITLE: Translational enhancers of EAAT2: therapeutic implications for neurodegenerative disease AUTHOR CONTACT: Nicholas Cosford
Sanford Burnham Institute for Medical Research, San Diego, CA, USA
Phone: (858) 795-5316; E-mail: ncosford@sanfordburnham.org View this article at: http://www.jci.org/articles/view/74608?key=c8cc94ae5cd76270cd4b Increased autophagy associated with BRAF inhibitor resistance BRAF inhibitors (BRAFi) are a first line treatment for BRAFV600E mutant melanoma; however, despite initial positive responses to treatment, nearly all patients develop BRAFi resistance. In this issue of the Journal of Clinical Investigation, Ravi Amaravadi and colleagues at the University of Pennsylvania found that BRAFi-resistant tumors exhibit higher levels of autophagy compared to baseline tumors and that the level of therapy-induced autophagy correlated with lower response rates and shorter progression-free survival times. The authors demonstrated that BRAFi therapy-associated autophagy is mediated by GRP78-dependent induction of ER stress. A combination of BRAF and autophagy inhibition promoted tumor regression in a murine xenograft model of BRAFi-resistant melanoma. In an accompanying Commentary, Shirish Shenolikar of Duke-NUS discusses how further work should be done to evaluate the combined use of BRAFi and autophagy inhibitors for melanoma treatment. TITLE: Targeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma AUTHOR CONTACT: Ravi Amaravadi
University of Pennsylvania, Philadelphia, PA, USA
Phone: 215-7965159; Fax: 2153498550; E-mail: ravi.amaravadi@uphs.upenn.edu View this article at: http://www.jci.org/articles/view/70454?key=bfd6c4375597db814525 ACCOMPANYING COMMENTARY TITLE: Dangerous liaisons: flirtations between oncogenic BRAF and GRP78 in drug-resistant melanomas AUTHOR CONTACT: Shirish Shenolikar
Duke University Medical Center, Singapore, UNK, USA
Phone: 65 6221 8625; E-mail: shirish.shenolikar@duke-NUS.edu.sg View this article at: http://www.jci.org/articles/view/74609?key=515044f4b58ac807d9b6 Dynamin 2 as a target for X-linked centronuclear myopathy X-linked centronuclear myopathy (XLCNM) is a muscle wasting disease with early onset and poor prognosis. XLCNM results from myotubularin (MTM1) loss-of-function mutations, while autosomal CNM can result from dynamin 2 (DNM2) dominant mutations. In this issue of the Journal of Clinical Investigation, Belinda Cowling and colleagues found that DNM2 levels were elevated in XLCNM patients and in a murine model of XLCNM. T Deletion of one copy of Dnm2 in Mtm1 mutant mice increased lifespan, whole body strength, and diaphragm function to levels similar to control animals. Additionally, muscle strength was increased and histological features were ameliorated or delayed. In the accompanying commentary, Alexis Demonbreun and Elizabeth McNally of the University of Chicago discuss the cellular mechanisms underlying DNM2s effects in XLCNM. TITLE: Reducing dynamin 2 expression rescues X-linked centronuclear myopathy AUTHOR CONTACT: Jocelyn Laporte
IGBMC, Illkirch, , FRA
Phone: +33388653412; E-mail: jocelyn@igbmc.fr View this article at: http://www.jci.org/articles/view/71206?key=77ef1ef003b721a906ca ACCOMPANYING COMMENTARY TITLE: Dynamin 2 the rescue for centronuclear myopathy AUTHOR CONTACT: Elizabeth McNally
University of Chicago, Chicago, IL, USA
Phone: 773 702 2672; Fax: 773 702 2681; E-mail: emcnally@uchicago.edu View this article at: http://www.jci.org/articles/view/74434?key=fdce72c440c2c6e09783 Lung allograft acceptance mediated by a CD8+ T cell population Rejection of grafted organs, especially lungs, is a major obstacle for transplantation therapy. Memory CD8+ T cell responses are believed to play a critical role in the rejection of transplanted organs and new pre-clinical protocols that specifically target memory T cell populations are currently in development. In this issue of the Journal of Clinical Investigation, Daniel Kreisel and colleagues at Washington University demonstrated that lung allograft acceptance in a murine lung allograft model is actually dependent on graft infiltration by central memory CD8+ T cells. Using two-photon intravital microscopy, Krupnick and colleagues found that T cell expression of the chemokine CCR7 was required for stable interactions with antigen presenting cells in murine lung allograft recipients. The interactions between T cells and antigen-presenting cells resulted in IFNγ and NO production, and subsequent dampening of the immune response. In an accompanying Commentary, Xinguo Jiang and Mark R. Nicolls of Stanford University discuss how these findings impact our understanding of the mechanisms underlying lung allograft acceptance. TITLE: Central memory CD8+ T lymphocytes mediate lung allograft acceptance AUTHOR CONTACT: Daniel Kreisel
Washington University in St. Louis, St. Louis, MO, USA
Phone: (314) 362-6021; Fax: (314) 367-8459; E-mail: kreiseld@wudosis.wustl.edu View this article at: http://www.jci.org/articles/view/71359?key=f503f89f1d56bceb2497 ACCOMPANYING COMMENTARY TITLE: Working toward immune tolerance in lung transplantation AUTHOR CONTACT: Mark Nicolls
Stanford University, Palo Alto, CA, USA
Phone: 650 493 5000 ext 69289; Fax: 650 849 0553; E-mail: mnicolls@stanford.edu View this article at: http://www.jci.org/articles/view/74701?key=5d398f75f71295aedccd Identification of an immune cell trafficking pathway in the CNS The central nervous system (CNS) is an immune privileged site; however, the mechanisms that confer this privilege are poorly understood. Failure of the CNS to maintain an anti-inflammatory state results in multiple sclerosis (MS) and other disease states. In this issue of the Journal of Clinical Investigation, David Brown and colleagues at the University of New South Wales identified a pathway for CNS immune cell traffic that is associated with the rostral migratory stream (RMS), a neuronal stem cell pathway that originates in the subventricular zone (SVZ) and extends to the olfactory bulb. From here, dendritic cells (DCs) migrate to the cervical lymph nodes where a subset increases T-regulatory cell activity, reducing anti-CNS autoimmune responses in mice. Importantly, disrupting this pathway leads to retention of DCs in the brain and increases cervical lymph node anti-CNS autoimmune responses. As a consequence CNS immune tolerance is broken resulting in spontaneous experimental autoimmune encephalitits and associated neuronal destruction. In the accompanying commentary, Gianvito Martino and colleagues at the San Raffaele Scientific Institute discuss the role of the SVZ in neuroprotection. TITLE: Immune cell trafficking from the brain maintains CNS immune tolerance AUTHOR CONTACT: David Brown
St Vincent's Hospital and University of New South Wales, Sydney, UNK, AUS
Phone: +61283824952 ; E-mail: D.Brown@amr.org.au View this article at: http://www.jci.org/articles/view/71544?key=1bc221523a5de81aa48e ACCOMPANYING COMMENTARY TITLE: AUTHOR CONTACT: Gianvito Martino
San Raffaele Scientific Institute, Milan, UNK, ITA
Phone: 39 (02) 2643 4853 (4854/4867); Fax: ; E-mail: martino.gianvito@hsr.it View this article at: http://www.jci.org/articles/view/74419?key=46c3cb90fe4406f3bd42 Macrophages promote neonatal heart regeneration Heart damage associated with myocardial infarction (MI) instigates an immune-mediated wound healing response that clears debris and restores tissue integrity, but also leads to fibrotic scarring, pathological remodeling, and a decline in cardiac function. In contrast, damaged neonatal mouse heart can regenerate without scarring, but this capacity is lost by postnatal day 7 (P7). In this issue of the Journal of Clinical Investigation, Eric Olson and colleagues at the University of Texas Southwestern Medical Center compared the immune response to heart damage in mice at P1 and P14 and found that heart regeneration following MI is dependent on a neonatal macrophage response. Further characterization of these cells revealed that regenerative macrophages secrete soluble factors that may play a role in regeneration. In the accompanying commentary, Paul Riley proposes that a better understanding of the immune modulators that promote regeneration could potentially be exploited to induce regeneration in adult heart. TITLE: Macrophages are required for neonatal heart regeneration AUTHOR CONTACT: Eric N. Olson
University of Texas Southwestern Medical Center, Dallas, TX, USA
Phone: 214 648-1187; Fax: 214 648-1196; E-mail: Eric.Olson@utsouthwestern.edu View this article at: http://www.jci.org/articles/view/72181?key=38c294228fd2cdc0468d ACCOMPANYING COMMENTARY TITLE: Fanning the flames to regenerate the heart AUTHOR CONTACT: Paul Riley
University of Oxford, Oxford, , GBR
Phone: +44 (0) 1865 282366; E-mail: paul.riley@dpag.ox.ac.uk View this article at: http://www.jci.org/articles/view/74418?key=42e0fc96737fb581b861 ALSO IN THIS ISSUE TITLE: Serum IgE clearance is facilitated by human FcεRI internalization AUTHOR CONTACT: Jeoung-Sook Shin
University of California, San Francisco, San Francisco, CA, USA
Phone: 415-476-5451; Fax: 415-476-3939; E-mail:
View this article at: http://www.jci.org/articles/view/68964?key=bfbb02fc77699af75d78 TITLE: Cell-specific translational profiling in acute kidney injury AUTHOR CONTACT: Jing Liu
University of Southern California, Los Angeles, CA, USA
Phone: 303 442 8077; E-mail: jing.liu@med.usc.edu View this article at: http://www.jci.org/articles/view/72126?key=cf371f40c1dca4812171 INFORMATION: END