Articles in 2010

Excessive glutamate seen in multiple sclerosis leads to excitotoxicity and neuronal dysfunction. Fallarino et al. find that the clinical signs and neuroinflammation in experimental autoimmune encephalitis is worsened in mice deficient in the metabotropic glutamate receptor-4. Small molecules that enhance signaling through this receptor suppress neuroinflammation by promoting T regulatory cell development and suppressing T_H17 responses. This cross-talk between the nervous and immune system suggests an endogenous mechanism to suppress neuroinflammation in the context of multiple sclerosis.

Increased levels of Ca²⁺ in cardiomyocytes promote cell growth that, under stressful conditions, such as those caused by hypertension, can contribute to heart remodeling and failure. Joerg Heineke et al. identify a new regulator of this type of maladaptive cardiac muscle growth in mice, the calcium-binding protein CIB1, which they show regulates the membrane-association of calcineurin and downstream signaling.

Dendritic cells in individuals with cancer and in mouse tumor models show an increase in triacylglycerides that seems to impair their antigen-processing capability and could thus contribute to tumor immune tolerance. This aberrant lipid load results from tumor-induced elevation of the scavenger receptor Msr1 on dendritic cells, and it can be targeted therapeutically to improve the efficiency of anticancer vaccines.

The authors uncover a new role for the RNA-binding protein Msi2 in the regulation of hematopoietic stem cell homeostasis and leukemogenesis. Msi2 is required for the maintenance of the balance between progenitor renewal and differentiation, and its overexpression cooperates with oncogenic events to induce aggressive leukemia. Msi2 expression is also elevated in human myeloid leukemias and may be a new prognostic marker and therapeutic target in acute myeloid leukemia.

Candida albicans is a fungal pathogen that causes serious systemic and mucosal infections in immunocompromised people. Blocking acetylation of histone H3 sensitizes C. albicans to antifungal agents, pointing to a new therapeutic strategy.

A prognostic gene expression signature predicts metastasis in individuals with sarcomas and other tumor types more accurately than existing tools.

Spinal cord injury leads to flaccid paralysis resulting from the loss of descending serotonergic modulation. Murray et al. demonstrate that spontaneous recovery of motoneuron excitability is associated with alternative mRNA editing and increased expression of constitutively active 5HT_2C serotonin receptors. Activation of these receptors leads to large persistent calcium currents, sustained muscle contractions and restoration of locomotion. However, in the absence of descending modulation from the brain, this leads to spasticity. Inhibiting constitutive 5-HT receptor activity is effective in reducing spasticity in rats and humans following spinal cord injury.

Basophils initiate T helper type 2 responses after exposure to allergens and IgE immune complexes. Juan Rivera and his colleagues find that elevated amounts of IgE in Lyn^−/− mice drive basophil activation, secretion of T helper type 2 cytokines and production of autoantibodies, leading to a lupus-like phenotype in mice and to glomerulonephritis. Depletion of basophils or deficiencies in IgE or interleukin-4 are sufficient to reduce autoantibody production and prevent kidney damage. Data from subjects with SLE suggest that increased IgE levels and activated basophils may contribute to disease.

The transcription factor ATF5 is associated with malignancy in glioblastomas. In this report, the authors devise a unique shRNA screen to identify and characterize the upstream regulators and downstream effectors of ATF5 in brain tumors. ATF5 upregulation is mediated by a concomitant increase in FRS2, PAK1 and CREB3L2 and promotes survival by elevating Mcl1 expression. This pathway represents a novel therapeutic target validated by the antitumor efficiency of the Raf kinase inhibitor sorafenib.

In two studies from teams led by Hiroshi Kawaguchi and Jang-Soo Chun, a role for HIF-2α in osteoarthritis has been uncovered. Along with identifying the molecular mechanism, the teams found that HIF-2α expression is increased in human osteoarthritic tissue, and mice deficient for the protein are protected in two osteoarthritis models, suggesting that HIF-2A could be a therapeutic target.

In two studies from teams led by Hiroshi Kawaguchi and Jang-Soo Chun, a role for HIF-2α in osteoarthritis has been uncovered. Along with identifying the molecular mechanism, the teams found that HIF-2α expression is increased in human osteoarthritic tissue, and mice deficient for the protein are protected in two osteoarthritis models, suggesting that HIF-2α could be a therapeutic target.

Rubin Tuder and his colleagues show that cigarette smoke induces expression of Rtp801 (also known as Redd1), a hypoxia-inducible protein that inhibits mTOR activity and enhances oxidative stress–mediated cell death. They also show that mice deficient in Rtp801 are protected from cigarette smoke–induced lung injury, thus suggesting the protein as a target to prevent emphysema.

This study dissects the contribution of TLR signaling to intestinal tumorigenesis. MyD88 signaling, known to be required for tumorigenesis in Apc^min/+ mice, is shown to be triggered by ligands from the microflora. MyD88-mediated activation of the MEK-ERK cascade stabilizes c-Myc by preventing its ubiquitin-mediated degradation. The findings link oncogenic c-Myc function to immune signaling and uncover MEK inhibition as a new therapeutic strategy to treat intestinal tumors.

In this work, Björn Lamprecht et al. found that survival of Hodgkin's lymphoma cells requires activity of the growth factor receptor CSF1R. Transcription of the gene encoding CSF1R was unexpectedly discovered to originate in a specific class of long terminal repeat, a type of repetitive element present in the genome. Transcriptional initiation from this class of long terminal repeats was widely activated in Hodgkin's lymphoma cells, which the authors traced to defects in epigenetic silencing (517–518).

Innate immune responses markedly affect subsequent adaptive responses. Here the authors show that adaptive immunity in the form of memory CD4⁺ T cells can also affect the magnitude of innate inflammatory responses.

Inappropriate wound healing can lead to fibrosis of an organ and interference with its proper function. Joseph Bonventre and his colleagues have found that G2/M cell cycle arrest of tubular epithelial cells in the kidney after acute injury leads to fibrosis and that targeting this arrest, or the signaling that results from this arrest, is ameliorative for disease progression (pages 523–525 and 544–550).

Wound repair involves the proper regeneration of the extracellular matrix. When this process goes awry, organ fibrosis results, damaging the organ's function. Now, Michael Zeisberg and his colleagues have uncovered an epigenetic mechanism by which kidney fibrosis occurs, as well as a potential new therapeutic target to prevent it (pages 523–525 and pages 535–543).

Giardia lamblia is a major intestinal pathogen causing acute or chronic diarrhea. It is thought to evade the immune system by switching its expression of the variant-specific surface protein (VSP), resulting in antigenic variation. Rivero et al. now report that by interfering with the machinery that restricts VSP expression, they can subvert antigenic variation and generate trophozoites that simultaneously express many VSPs and induce broadly reactive immunity against infection with various G. lamblia isolates (pages 522–523).

T cell receptor (TCR) gene therapy is a promising immunotherapy for cancer and infectious disease. But introducing exogenous TCR α and β chains into T cells may have unintended consequences. In this issue, Bendle et al. show that the transfer of TCR-transduced T cells into mice triggered a lethal pathology that resembles graft-versus-host disease and is caused by the pairing of endogenous and exogenous TCR chains resulting in autoreactive T cells (pages 520–521).

Individuals with the disease hereditary hemorrhagic telangiectasia have vascular defects that lead to frequent hemorrhages. Franck Lebrin et al. now show that thalidomide, tested as a therapy in a small set of individuals with this disease, lowers the frequency of hemorrhaging and the need for blood transfusions. The authors tie the antihemorrhagic effects of thalidomide to its ability to promote blood vessel maturation through effects on PDGF-B expression by endothelial cells and on pericyte cell proliferation (pages 370–372).