Articles in 2009

Sterol metabolism modulates immune responses through liver X receptor activation. Tumors harness this signaling pathway and can escape immunosurveillance by inhibiting dendritic cell migration to tumor-draining lymph nodes.

The virus HTLV-1 is thought to pass between cells through synapses formed when infected lymphocytes make contact with other T cells. Isabelle Thoulouze and her colleagues uncover an alternative mechanism for the cell-to-cell transmission of this virus. They show that HTLV-1 virions bud at the plasma membrane and are held at the cell surface in structures reminiscent of bacterial biofilms. When infected lymphocytes make contacts with other cells, the adhesive viral assemblies are rapidly transferred to to the surface of the new lymphocyte, from which the virions mediate a new round of infection.

The circadian clock controls many aspects of human physiology, and disturbances in circadian rhythms have been linked to cardiovascular disease. Masao Doi et al. now delineate a new pathway by which the circadian clock influences hormone production and blood pressure in mice—clock genes control expression of an aldosterone biosynthetic enzyme, such that increased activity of this enzyme in mice with a disrupted circadian clock may account for the increased aldosterone levels and salt-sensitive hypertension seen in these mice.

Premature infants can suffer from an anatomical defect in which the ductus arteriosus, a blood vessel that connects the pulmonary artery and the aorta during fetal development, fails to close at birth. Katrin Echtler et al. now show that platelets are needed for closure in mice and that reduced platelet function may be clinically relevant: in a retrospective study of preterm human infants, low platelet counts were associated with the presence of an unclosed ductus arteriosus.

Mutations in NOD2—a bacterial sensor in dendritic cells—and mutations in genes related to autophagosome function have been linked to Crohn's disease. Alison Simmons and her colleagues link these susceptibility genes in a single functional pathway. They show that triggering of NOD2 induces autophagy, resulting in increased bacterial antigen presentation on the surface of the dendritic cell. They also show that this process goes awry in dendritic cells expressing the susceptibility variants from individuals with Crohn's disease.

Gökhan Hotamisligil and his colleagues report that reducing endoplasmic reticulum stress in macrophages by targeting the lipid chaperone aP2 ameliorates atherosclerosis in a mouse model, paving the way for a possible new clinical therapy.

Contrary to the widely held view that impaired γ-aminobutyric acid (GABA)-mediated neurotransmission underlies epileptic activity, extrasynaptic GABA-dependent thalamocortical inhibition caused by reduced GABA uptake is reported to be increased in diverse models of absence seizures.

Gallo and his colleagues report that commensal bacteria on the skin help to dampen inflammation caused by skin injury in mice. They show that, after wounding, necrotic cells release RNA that triggers TLR3 on keratinocytes, causing inflammatory cytokine release. Commensal bacteria in the skin suppress this inflammatory response through triggering TLR2 on the keratinocytes.

Excitotoxicity mediated by over activation of glutamate receptors results in neuronal loss after ischemia. Activation of sterol regulatory element–binding protein-1 is now shown to be crucial for glutamate-mediated excitotoxic neuronal death in a mouse model of stroke.

By taking advantage of the direct interaction between heat shock protein 90 (Hsp90) and the transcriptional repressor Bcl-6, a purine-derived inhibitor of Hsp90 selectively kills diffuse large B cell lymphomas that depend on the expression of Bcl-6 for their survival.

In individuals with 5q– syndrome, deletion within chromosome 5q is associated with hematological abnormalities. Jillian Barlow et al. now create an animal model of the disease using chromosomal engineering to remove a corresponding region of the mouse genome. The resulting hematological abnormalities resemble those in the human disease, and the authors provide genetic evidence that p53 activation contributes to the disease process.

In a mouse model of Huntington's disease, synaptic activation of NMDA receptors induces the formation of huntingtin-containing inclusions, rendering neurons more resistant to death in vivo and in vitro. In contrast, stimulation of extrasynaptic NMDA receptors increases neuronal vulnerability by preventing inclusion formation.

For myelodysplastic syndromes caused by deletion of chromosome 5q, Daniel Starczynowski et al. provide evidence that decreased expression of two miRNAs in this region—miR-145 and miR-146a—contributes to abnormal megakaryocyte differentiation and platelet production and progression of the disease to either bone marrow failure or leukemia. The authors also provide a mechanistic explanation for these effects by which loss of these two miRNAs leads to derepression of innate immune signaling.

Rheumatoid arthritis usually begins in one joint but spreads to other joints as the disease progresses. Elena Neumann and her colleagues show that rheumatoid arthritis synovial fibroblasts (RASFs) may be key mediators of this process. They show, using a SCID mouse model, that human RASFs can migrate long distances through the bloodstream from diseased cartilage to unaffected cartilage, where they can mount a new attack.

Vascular defects resulting from pericyte cell death are thought to be a major underlying cause of diabetic retinopathy. Pedro Geraldes et al. investigate the signaling mechanisms by which hyperglycemia leads to pericyte death and delineate a pathway by which PKC-δ activation decreases antiapoptotic PDGF receptor signaling (pages 1248–1249).

David Hassel et al. show that mutations affecting the protein nexilin underlie an unusual type of dilated cardiomyopathy characterized by disrupted Z-disk structures in cardiac muscle. Functional studies in zebrafish revealed that nexilin has an essential role in maintaining Z-disk stability and suggested that the disease-causing nexilin mutations found in humans encode proteins that act in a dominant-negative fashion.

Notch signaling is known to modulate the phenotype of vascular smooth muscle cells. Xiaodong Li et al. now provide evidence for the importance of signaling through the NOTCH3 receptor and its downstream target HES-5 in pulmonary arterial smooth muscle cells for the development of pulmonary arterial hypertension, and they demonstrate the therapeutic potential of targeting this signaling pathway in a mouse model of pulmonary hypertension.

Soman Abraham and his colleagues report a new mechanism of immune suppression used by Salmonella. The bacteria traffic to lymph nodes, where Salmonella lipopolysaccharide triggers the downmodulation of certain chemokines, disrupting the cellular organization of the lymph node and impairing adaptive immunity.

Macrophages coordinate the disposal of apoptotic cells. Ajay Chawla and his colleagues show that PPAR-δ, a sensor of fatty acids, is involved in this process. Ingestion of apoptotic cells by macrophages prompts the upregulation of PPAR-δ, which then responds by enhancing the expression of opsonins. Lack of PPAR-δ reduces apoptotic cell clearance and predisposes to autoimmunity (pages 1246–1248).

Chemotherapy often leads to premature death of oocytes, and thus infertility, in young individuals with cancer. Here, Stefania Gonfloni and her colleagues show that chemotherapy-induced activation of the kinase c-Abl is responsible for this oocyte failure and that, in vivo, the c-Abl inhibitor imatinib prevents this effect (pages 1124–1125).