Public Release:  JCI online early table of contents: June 15, 2009

Journal of Clinical Investigation

EDITOR'S PICK: Therapeutic delivery of a gene to dysfunctional nerves

Medical conditions that affect sensory nerves outside the brain and spinal cord are known as sensory neuronopathies. These conditions, which are extremely painful, include shingles and can be caused by anticancer drugs such as cisplatin. In many sensory neuronopathies, the nerves that are dysfunctional are those in a region of the body known as the dorsal root ganglion (DRG), and these conditions are particularly difficult to treat. However, Lawrence Chan and colleagues, at Baylor College of Medicine, Houston, have developed an approach to target therapeutic genes to nerves in the DRG, and used it to reduce sensory nerve dysfunction in a mouse model of Sandhoff disease, an inherited condition in which many nerves, including those in the DRG, are affected.

The authors developed a system to generate helper-dependent adenoviruses that targeted only DRG nerves. These were used to deliver genes to DRG nerves in mice and found to be dramatically more efficient at gene delivery than nontargeted helper-dependent adenoviruses. In mice lacking the Hexb gene, which are consider a mouse model of Sandhoff disease, administration of DRG-targeted helper-dependent adenoviruses carrying the Hexb gene restored Hexb expression in DRG nerves and eliminated sensory nerve dysfunction. The authors hope this approach could be developed for treating different forms of DRG sensory neuronopathies.

TITLE: DRG-targeted helper-dependent adenoviruses mediate selective gene delivery for therapeutic rescue of sensory neuronopathies in mice

AUTHOR CONTACT:
Lawrence Chan
Baylor College of Medicine, Houston, Texas, USA.
Phone: (713) 798-4478; Fax: (713) 798-8764; E-mail: lchan@bcm.tmc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=39038


IMMUNOLOGY: Bacteria are first sensed by cells lining blood vessels, not immune cells

Paul Kubes and colleagues, at the University of Calgary, Canada, have provided evidence in mice to refute the paradigm that the initial phase of the immune response to infection with Gram-negative bacteria (the recruitment of immune cells known as neutrophils to the site of infection) is triggered following immune sentinel-cell recognition of the bacterial molecule LPS via the protein TLR4. Rather, the researchers found that LPS recognition by TLR4 on the cells that line blood vessels (endothelial cells) is the crucial event that initiates neutrophil recruitment and bacterial clearance in mice.

In the study, mice engineered such that they expressed TLR4 exclusively on endothelial cells were found to be dramatically less susceptible to a lethal intraperitoneal dose of the bacterium E. coli than normal mice. This was because neutrophil recruitment to the site of infection was much more efficient in the engineered mice than in normal mice, as a result of many neutrophils being sequestered in the blood vessels of the lungs of normal mice. In contrast, TLR4 on endothelial cells was not involved in neutrophil recruitment following LPS administration into the airways, rather TLR4 on immune sentinel cells was the key trigger of neutrophil recruitment. The authors therefore conclude that TLR4 on endothelial and immune sentinel cells is crucial for infection with Gram-negative bacteria at different sites, the blood and tissues, and the lungs, respectively.

TITLE: Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection

AUTHOR CONTACT:
Paul Kubes
University of Calgary, Calgary, Alberta, Canada.
Phone: (403) 220-8558; Fax: (403) 270-7516; E-mail: pkubes@ucalgary.ca.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36411


CARDIOLOGY: New support for a controversial mechanism underlying an irregular heart beat

The most common form of human heart beat irregularity (atrial fibrillation) can be fatal if left untreated. It has been suggested that it is caused, in part, by calcium leaking from a cellular store in heart cells, potentially through the RyR2 channel, although this mechanism remains controversial. However, a team of researchers at Baylor College of Medicine, Houston, and Dresden University of Technology, Germany, has provided support for this hypothesis by showing that the protein CaMKII can enhance RyR2-mediated calcium leak, promoting atrial fibrillation in mice.

The team, led by Xander Wehrens and Dobromir Dobrev, studied mice engineered to express a mutant form of RyR2 associated with calcium leak. Although these mice did not spontaneously develop atrial fibrillation, they were more likely to develop atrial fibrillation than normal mice if their heart rate was forced up. This was related to the functional interaction of CaMKII with RyR2, and blocking CaMKII function in these mice prevented them from developing atrial fibrillation when their heart rate was forced up. As a functional link between CaMKII and RyR2 was observed in heart biopsies from patients with chronic atrial fibrillation, the authors suggest that enhanced CaMKII function might increase calcium leakage via RyR2 and initiate clinical atrial fibrillation.

TITLE: Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice

AUTHOR CONTACT:

Xander H.T. Wehrens
Baylor College of Medicine, Houston, Texas, USA.
Phone: (713) 798-4261; Fax: (713) 798-3475; E-mail: wehrens@bcm.edu.

Dobromir Dobrev
Dresden University of Technology, Dresden, Germany.
Phone: 49-351-458-6279; Fax: 49-351-458-6315; E-mail: dobrev@rcs.urz.tu-dresden.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37059


HEPATOLOGY:Inflammatory molecules promote liver scarring

Scarring of the liver, which can progress to cirrhosis and/or cancer of the liver, is caused by persistent liver damage, such as occurs in those with untreated hepatitis C or alcoholism. Although such scarring (fibrosis) develops in an inflammatory environment, the role of inflammatory molecules has not been well defined. However, a team of researchers at Columbia University, New York, and UCSD, La Jolla, has established that the proteins CCR1 and CCR5 and the soluble inflammatory molecules that bind to them promote the development of liver fibrosis in mice.

The team, led by Robert Schwabe and Ekihiro Seki, observed that expression of the inflammatory molecules MIP-1-alpha, MIP-1-beta, and RANTES, and the proteins to which they bind (CCR1 and CCR5), was increased in 2 mouse models of liver fibrosis. Consistent with a role for these molecules in the development of liver fibrosis, preventing the inflammatory molecules binding CCR1 and CCR5 reduced liver fibrosis, as did eliminating expression of either CCR1 or CCR5. The latter experiments also identified the cells on which CCR1 and CCR5 expression is important for promoting liver fibrosis. As expression of RANTES, CCR1, and CCR5 was detected in the livers of patients with cirrhosis, the authors suggest that targeting CCR1 and CCR5 (for which there are already small molecule inhibitors in clinical development) might be a viable approach to prevent liver fibrosis.

TITLE: CCR1 and CCR5 promote hepatic fibrosis in mice

AUTHOR CONTACT:

Robert F. Schwabe
Columbia University, New York, New York, USA.
Phone: (212) 851-5462; Fax: (212) 851-5461; E-mail: rfs2102@columbia.edu.

Ekihiro Seki
University of California, San Diego, La Jolla, California, USA.
Phone: (858) 822-5339; Fax: (858) 822-5370; E-mail: ekseki@ucsd.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37444


HEPATOLOGY: Normal development of cells with abnormal numbers of nuclei

Most of our cells contain a single nucleus that harbors 46 chromosomes (DNA and protein complexes that contain our genes). However, during normal postnatal development, liver cells containing two nuclei, each of which have 46 chromosomes, appear. These cells, which are known as binucleated tetraploid hepatocytes, arise in all mammals as a result of failure of the cellular process cytokinesis (the process by which the bulk of a cell, excluding the nucleus, divides to form two "daughter" cells). New insight into the failure of this process has now been provided by Chantal Desdouets and colleagues, at Institut Cochin, France, who have identified a cellular signaling pathway that leads to cytokinesis failure and the formation of binucleated tetraploid hepatocytes in rodents.

Initial analysis revealed that weaning triggered the initiation of cytokinesis failure and formation of binucleated tetraploid hepatocytes in rats. Follow up studies in mice and rats indicated that the aspect of the suckling-to-weaning transition that controls the initiation of cytokinesis failure is the increase in insulin levels that occurs upon weaning. Further in vitro analysis, using pharmacological inhibitors, determined the signaling pathway by which insulin controlled cytokinesis failure. Future studies will investigate whether the deregulation of the insulin signaling pathway observed in various metabolic diseases alters the number of binucleated tetraploid hepatocytes in the liver ploidy profile and whether this has a role in disease.

TITLE: The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents

AUTHOR CONTACT:
Chantal Desdouets
Institut Cochin, Université Paris Descartes, Paris, France.
Phone: 33-1-44-41-24-39; Fax: 33-1-44-41-24-21; E-mail: chantal.desdouets@inserm.fr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=38677


BACTERIOLOGY: Bacteria can induce a harmful immune response

Molecules known as type I IFNs are a central component of the protective immune response following infection with a virus. In contrast, these molecules are not normally linked to the protective immune response following infection with the bacterium Staphylococcus aureus, which is becoming a major health problem due to the emergence of methicillin-resistant (MRSA) strains. However, Alice Prince and colleagues have now determined that Staphylococcus aureus induce the production of type I IFNs by mouse and human airway cells, but these molecules are not part of a protective immune response in mice, rather they markedly enhance the severity of the pneumonia caused by Staphylococcus aureus infection.

In the study, the researchers were able to pin down the Staphylococcus aureus protein that causes mouse and human airway cells to produce type I IFNs, protein A. Further analysis identified the region of protein A responsible, the Xr domain, and determined the importance of the type I IFNs produced -- mice lacking the molecule to which most type I IFNs bind were dramatically protected from lethal pneumonia caused by infection with Staphylococcus aureus. As the signaling pathway by which type I IFNs activate their effects is very well defined, the authors suggest that targeting molecules in this pathway might provide a beneficial therapeutic approach for treating pneumonia caused by Staphylococcus aureus infection.

TITLE: Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A

AUTHOR CONTACT:
Alice Prince
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 305-4193; Fax: (212) 342-5728; E-mail: asp7@columbia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35879


VASCULAR BIOLOGY: Blood-borne molecule helps regulate blood-vessel integrity

Although maintaining the integrity of blood vessel walls is essential for life, well-controlled temporary leakage of blood contents through the walls of blood vessels into the tissues is a hallmark of inflammation. Although the molecule S1P is known to act on the cells that line blood vessels (endothelial cells) to regulate the permeability of blood vessel walls, the in vivo source of SIP in this process remains unknown, and whether it has a role in inflammation has not been determined. In a new study, Shaun Coughlin and colleagues, at UCSF, San Francisco, have shed light on these issues, revealing that mice that lack S1P selectively in plasma (the liquid component of blood) have increased leakage from the blood vessels in response to a variety of stimuli, including inflammatory ones. As the leakage was reversed by treatment with either S1P-containing red blood cells or an agonist for the protein to which SIP binds, the authors conclude that S1P in the blood regulates blood-vessel integrity and prevents potentially lethal decreases in blood volume after exposure to leak-inducing stimuli.

TITLE: Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice

AUTHOR CONTACT:
Shaun R. Coughlin
University of California, San Francisco, San Francisco, USA.
Phone: (415) 476-6174; Fax: (415) 476-8173; E-mail: shaun.coughlin@ucsf.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=38575

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