EDITOR’S PICK: Cells in the lung clear the air to prevent lung damage
Air pollution and tobacco smoke contain oxidants that when inhaled can cause damage to the lungs and contribute to diseases such as asthma and chronic obstructive pulmonary disease (COPD). In a study that appears in the March issue of the Journal of Clinical Investigation, researchers from the Harvard School of Public Health, Boston, identify a new mechanism by which mice are protected against inhaled oxidants.
Lester Kobzik and colleagues observed that immune cells in the lungs (known as alveolar macrophages) of mice resistant to lung damage caused by the oxidant ozone expressed more of a protein known as MARCO than the alveolar macrophages of mice susceptible to ozone-induced lung damage. Consistent with a role for MARCO in protection from oxidant-induced lung damage, mice lacking MARCO showed more lung damage when exposed to either ozone or another oxidant than mice expressing normal amounts of MARCO. MARCO provided protection by enabling alveolar macrophages to take up lipids in the lung modified by the oxidant that would initiate an inflammatory reaction if not removed. A similar role in the removal of lipids in the lung modified by these oxidants was identified for another protein related to MARCO, SR-AI/II. As discussed in an accompanying commentary by Edward Postlethwait from the University of Alabama at Birmingham, it is now important to determine whether similar functions can be ascribed to these and other related proteins (all of which are known as scavenger receptors) in humans because of the extensive morbidity associated with lung diseases such as asthma and COPD.
TITLE: Protection against inhaled oxidants through scavenging of oxidized lipids by macrophages receptors MARCO and SR-AI/II
AUTHOR CONTACT:
Lester Kobzik
Harvard School of Public Health, Boston, Massachusetts, USA.
Phone: (617) 432-2247; Fax: (617) 432-0014; E-mail: lkobzik@hsph.harvard.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29968
ACCOMPANYING COMMENTARY
TITLE: Scavenger receptors clear the air
AUTHOR CONTACT:
Edward M. Postlethwait
University of Alabama at Birmingham, Birminghman, Alabama, USA.
Phone: (205) 934-7085; Fax: (205) 975-6341; E-mail: EPostlethwait@ms.soph.uab.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31549
METABOLIC DISEASE: What makes good cholesterol so “good” for us?
High levels of good cholesterol (high density lipoprotein (HDL)) are associated with protection from cardiovascular disease, which remains the leading cause of death in the United States. But what exactly makes HDL so “good” for us?
In an attempt to answer this question researchers from the University of Washington, Seattle, have determined exactly what proteins are contained within HDL and have identified a number of surprises; further analysis of which might provide new understanding of the mechanisms by which HDL provides protection from cardiovascular disease and lead to the development of both accurate indicators of disease risk and new treatments for this disease.
In the study, which appears in the March issue of the Journal of Clinical Investigation, Jay Heinecke and colleagues isolated HDL from both healthy individuals and individuals with coronary artery disease (CAD) and assessed the protein content of these large complexes by mass spectrometry. As well as the expected proteins involved in lipid metabolism, HDL from healthy individuals contained several proteins involved in the innate immune response (including complement proteins), several serine proteinase inhibitors, and many acute-phase inflammatory proteins. By contrast, HDL from patients with CAD contained high levels of the protein apoE, which is involved in lipoprotein transport. As discussed in the accompanying commentary by Muredach Reilly and Alan Tall, this study supports “the concept that HDL plays a role in innate immunity and in the regulation of proteolytic cascades involved in inflammatory and coagulation processes.” and “could eventually help in the development of biomarkers to predict the outcome of interventions that alter HDL levels and functions.”
TITLE: Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL
AUTHOR CONTACT:
Jay W. Heinecke
University of Washington, Seattle, Washington, USA.
Fax: (206) 685-8346; E-mail: heinecke@u.washington.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=26206
ACCOMPANYING COMMENTARY
TITLE: HDL proteomics: pot of gold or Pandora’s box?
AUTHOR CONTACT:
Muredach P. Reilly
University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-1214; Fax: (215) 573-2094; E-mail: muredach@itmat.gcrc.upenn.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31608
GENETICS: Genetic mutations cause CoQ10 enzyme deficiency
Individuals with a deficiency in a protein known as CoQ10 can be grouped into different categories depending on their clinical symptoms. Primary CoQ10 deficiency, that is a deficiency caused by a genetic mutation, can be treated by dietary CoQ10 supplementation. In a study that appears in the March issue of the Journal of Clinical Investigation, Agnès Rötig and colleagues from Hôpital Necker-Enfants Malades, France, have identified two new genetic mutations that cause CoQ10 deficiency. They showed that in one family individuals with a CoQ10 deficiency had a mutation in the gene PDSS1 and that in a second family individuals with a CoQ10 deficiency had a mutation in the gene COQ2. The genetic mutations led to the generation of non-functional forms of the proteins prenyldiphosphate synthase and OH-benzoate polyprenyltransferase, respectively, which are involved in the production of CoQ10. The authors hope that the identification of mutations in these two genes and the future “identification of disease-causing genes in other families will help to elucidate the clinical variability of [CoQ10 deficiency].”
In an accompanying commentary, Salvatore DiMauro and colleagues from Columbia University, New York, describe how the field has moved forward relatively slowly since the initial description of individuals with a CoQ10 deficiency in 1989, and discuss how these data and other recent findings have injected new hope that CoQ10 deficiency can be detected early and be treated with dietary CoQ10.
TITLE: Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders
AUTHOR CONTACT:
Agnès Rötig
Hôpital Necker-Enfants Malades, Paris, France.
Phone: +33-144-49-51-61; Fax: +33-147-34-85-14; E-mail: roetig@necker.fr.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29089
ACCOMPANYING COMMENTARY
TITLE: Mutations in coenzyme Q10 biosynthetic genes
AUTHOR CONTACT:
Salvatore DiMauro
Columbia University Medical Center, New York, New York, USA.
Phone: (212) 305-1662; Fax: (212) 305-3986; E-mail: sd12@columbia.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31423
IMMUNOLOGY: Natural antibodies in newborns recognize a limited spectrum of proteins
Although autoimmune diseases, which occur when the body’s immune system turns on itself, are often characterized by the presence of antibodies that recognize proteins of the tissue that it is under attack, healthy individuals also have a large number of circulating antibodies that can recognize proteins of their own tissues. These antibodies are known as natural antibodies and their origin, function, and precise specificity have not been clearly defined.
In a study that appears in the March issue of the Journal of Clinical Investigation, Irun Cohen and colleagues from the Weizmann Institute of Science, Israel, show that the spectrum of proteins recognized by natural IgM and IgA antibodies from a mother and her newborn child differ markedly. In addition, the spectrum of proteins recognized by natural IgM antibodies from several different newborn children was relatively uniform, whereas the spectrum of proteins recognized by the natural IgM antibodies from the mothers of these children showed no uniformity. Interestingly, some of the proteins recognized by the natural IgM antibodies from newborn children were proteins that are known to be targeted in autoimmune diseases, leading the authors to suggest that these natural IgM antibodies might provide the basis for the emergence of autoimmune diseases later in life. By contrast, in an accompanying commentary, Eric Meffre and Jane E. Salmon from Weill Medical College of Cornell University, New York, suggest that the natural IgM antibodies present in newborn children are protective and that autoimmunity arises as a result of “defects in the maturation of the immune system later in life.”
TITLE: Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics
AUTHOR CONTACT:
Irun R. Cohen
Weizmann Institute of Science, Rehovot, Israel.
Phone: +972-8-934-2911; Fax: +972-8-934-4103; E-mail: irun.cohen@weizmann.ac.il.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29943
ACCOMPANYING COMMENTARY
TITLE: Autoantibody selection and production in early human life
AUTHOR CONTACT:
Eric Meffre
Weill Medical College of Cornell University, New York, New York, USA.
Phone: (212) 774-2347; Fax: (212) 717-1192; E-mail: meffree@hss.edu.
Jane E. Salmon
Weill Medical College of Cornell University, New York, New York, USA.
Phone: (212) 606-1422; Fax: (212) 717-1192; E-mail: salmonj@hss.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=31578
NEPHROLOGY: How aldosterone keeps salt in the body
The hormone aldosterone regulates the amount of sodium (Na+) that we retain in our body and how much excrete in our urine by activating epithelial Na+ channels (ENaCs). In this way it has a major influence on blood pressure and extracellular fluid volume, thereby influencing the course of cardiovascular and renal diseases. Although it is known that aldosterone induces the expression of a protein known as SGK1 and that SGK1 can increase the expression of the alpha-subunit of ENaC (ENaC-alpha), the precise molecular details of this pathway have not been clearly determined.
In a study appearing in the March issue of the Journal of Clinical Investigation, Bruce Kone and colleagues from the University of Texas Medical School at Houston, demonstrate that in the mouse, SGK1 increases the expression of ENaC-alpha by phosphorylating a protein known as AF9. Unphosphorylated AF9 can bind a protein known as Dot1a and this complex sits on the promoter of the gene that encodes ENaC-alpha, by preventing histone methylation and thereby preventing the gene from being expressed. Upon phosphorylation by SGK1, the AF9-Dot1A complex breaks part, enabling high levels of the gene encoding ENaC-alpha to be expressed. This study therefore identifies the molecular pathway by which aldosterone activates ENaCs in the mouse and is likely to apply to other genes encoding proteins activated by aldosterone.
In an accompanying commentary, David Pearce and Thomas Kleyman clarify the importance of this study for our understanding of sodium retention and outline the questions that remain to be answered before this increased understanding can be translated to the development of drugs for the treatment of high blood pressure.
TITLE: Aldosterone-induced Sgk1 relieves Dot1a-Af9–mediated transcriptional repression of epithelial Na+ channel-alpha
AUTHOR CONTACT:
Bruce C. Kone
University of Texas Medical School at Houston, Houston, Texas, USA.
Phone: (713) 500-6500; Fax: (713) 500-6497; E-mail: bruce.c.kone@uth.tmc.edu.
Wenzheng Zhang
University of Texas Medical School at Houston, Houston, Texas, USA.
Phone: (713) 500-6500; Fax: (713) 500-6497; E-mail: Wenzheng.Zhang@uth.tmc.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29850
ACCOMPANYING COMMENTARY
TITLE: Salt, sodium channels, and SGK1
AUTHOR CONTACT:
Thomas R. Kleyman
University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Phone: (412) 647-3121; Fax: (412) 648-9166; E-mail: kleyman@pitt.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31538
Journal
Journal of Clinical Investigation