Articles in 2012

Vascular homeostasis in the lung is disturbed in pulmonary arterial hypertension. Jongmin Kim et al. delineate a new signaling axis controlling endothelial cell proliferation and cytokine production that is dysregulated in pulmonary endothelial cells from individuals with this disease. In this axis, the peptide apelin controls expression of the cytokine FGF2, a mitogen for endothelial and vascular smooth-muscle cells, through effects on two microRNAs. The authors also demonstrated the functional importance of these miRNAs in rat models of pulmonary hypertension.

The early events in the pathogenesis of type 1 diabetes remain incompletely understood. Julien Diana et al. now show that in response to physiological beta cell death, innate immune cells including neutrophils and B1-a cells are recruited early on to pancreatic islets. These cells promote interferon-α production by plasmacytoid dendritic cells in the pancreas, promoting autoreactive T cell responses and autoimmunity.

Whether the molecular drivers of tumor initiation are the same factors that promote metastasis during tumor progression is addressed in this report. In renal carcinoma, common primary driving alterations such as VHL loss do not necessarily correlate with outcome, and the authors show that additional epigenetic adaptations are required to unleash prometastatic behavior. Two important metastastic drivers, CXCR4 and CYTIP, are activated downstream of VHL loss through epigenetic reprogramming involving differential chromatin modification or DNA methylation, exemplifying the complex evolution of tumorigenic traits downstream of driving alterations.

In a new study Yingxian Li and her colleagues show that the microRNA miR-214 targets ATF4 in osteoblasts to negatively regulate their activity. Manipulating miR-214 levels experimentally showed that its elevated expression is sufficient to induce bone loss in mice and that its therapeutic inhibition reduces bone loss in two mouse models.

Gemcitabine and 5-fluorouracil are two commonly used chemotherapeutic agents for the treatment of cancer. François Ghiringhelli and colleagues now report that the antitumor efficacy of these agents is mitigated by myeloid derived suppressor cells (MDSCs). The authors show that these drugs can activate the NLRP3 inflammasome, leading to increased secretion of IL-1β by MDSCs and IL-17 production by CD4⁺ T cells, which can promote tumor growth.

The mechanism whereby activation of G protein–coupled receptors (GPCRs) increase the production of amyloid-β (Aβ) peptide remains unclear. Here Bart De Strooper and colleagues show that the GPCR adaptor protein β-arrestin 2 promotes Aβ production by associating with APH-1A and increasing γ-secretase activity. Overexpression of β-arrestin 2 increases Aβ generation, whereas mice lacking β-arrestin 2 have reduced amyloid accumulation. Moreover, expression of β-arrestin 2 is elevated in individuals with Alzheimer's disease, suggesting a potential therapeutic target aimed at reducing amyloid production.

Defects in mitochondrial function have been believed to contribute to insulin resistance. Myung-Shik Lee and colleagues now show that mitochondrial dysfunction in muscle induced by tissue-specific deficiency of autophagy results in upregulation of Fgf21 and improved metabolism, suggesting that at least some mitochondrial dysfunction may actually be beneficial.

Oncolytic virotherapy has been tested in cancer patients, but its efficacy is uncertain. Alvarez-Breckenridge et al. now report that in mouse models of glioblastoma, an antiviral response mediated by natural killer (NK) cells may impair the anticancer efficacy of oncolytic virotherapy. Their findings suggest that limiting the cytolytic activity of NK cells might enhance replication of oncolytic viruses and increase tumor cell killing.

Proinflammatory cytokine expression increases as a result of amyloid deposition in Alzheimer's disease. Frank L. Heppner and colleagues show that genetic and pharmacological inhibition of IL-12 and IL-23 signaling reduces plaque load and improves cognitive deficits in mouse models of Alzheimer's disease. As the concentration of p40 is also increased in the cerebrospinal fluid of individuals with Alzheimer's disease, this suggests that this pathway may be targeted therapeutically in patients.

The peptidase DPP4 has a wide variety of target proteins, including the chemokine SDF-1 and the hormone GLP-1. Hal Broxmeyer and his coworkers now identify colony-stimulating factors as a new class of DPP4 substrates, including GM-CSF, G-CSF, IL-3 and erythropoietin. Treatment of mice with a clinically approved, orally available DPP4 inhibitor improved hematopoietic recovery after radiation or chemotherapeutic drug administration, pointing to potential clinical applications of these findings.

Axonal and neuronal damage are commonly seen in patients with multiple sclerosis. Manuel A. Friese and his colleagues now report that the cation channel transient receptor potential melastatin 4 (TRPM4) is upregulated in multiple sclerosis lesions in patients and contributes to disease in vivo. Genetic deletion or pharmacological inhibition of TRPM4 in a mouse model of multiple sclerosis reduces clinical scores and is neuroprotective, suggesting this may represent a novel therapeutic target.

Hydrocephalus is a neurological disorder characterized by expansion of the ventricles. In a mouse model, the authors identified a role for neural progenitors and for platelet-derived growth factor signaling in the pathogenesis of neonatal hydrocephalus. Targeting this pathway reduced ventricular volume, pointing to a new therapeutic target for this condition.

A molecular mechanism in the brain and individual tissues allows mammals to adapt to a 24-hour clock. Garret FitzGerald and colleagues now show that genetic deletion of one member of this pathway specifically in the fat of mice results in acutely altered lipid profiles that, in turn, result in increased feeding and obesity. This could explain why human night-shift workers are at an increased risk for obesity and metabolic disease.

Attenuated viruses can be highly effective vaccines. In this issue, Ralph Baric and colleagues report that inactivating mutations in the exonuclease ExoN of a mouse-adapted SARS coronavirus impair replication fidelity and cause a mutator phenotype. The resulting attenuated virus protected mice against a lethal coronavirus challenge.

Hematopoietic stem cells are difficult to maintain in vitro, hampering their clinical use. Jian Huang et al. show that mouse and human hematopoietic stem cells can be maintained in culture in the absence of exogenous cytokines by combined treatment with agents that activate Wnt and inhibit mTOR signaling, two major signaling pathways implicated in stem cell homeostasis. Moreover, treatment with two such compounds used clinically increases the number of hematopoietic stem cells in mice in vivo.

Obesity is often marked by chronic, low-grade inflammation, which is believed to contribute to metabolic disturbances associated with this condition. Chih-Hao Lee and colleagues show that injection of a known immunomodulatory glycan, one found in mother's milk and in S. mansoni egg extract, results in improved metabolic function of the adipose tissue and liver in a mouse dietary-mediated obesity model.

The chromatin-modifying protein SIRT6 has previously been shown to have anti-aging properties. Sundaresan et al. now show that SIRT6 expression is low in failing human hearts and SIRT6 in mice protects the heart by suppressing the activity of the c-Jun transcription factor, which acts as a global regulator of genes encoding components of the IGF-Akt signaling pathway.

The self renewal of hematopoietic stem cells is regulated by the bone marrow microenvironment. Whereas previous studies have focused on the role of osteoblasts, Ingrid Winkler et al. now show that bone marrow endothelial cells in the so-called 'vascular niche' contribute to this regulation by directly inducing HSC proliferation. In mice, deficiency or antagonism of the endothelial-specific adhesion protein E-selectin promotes HSC quiescence and self renewal. These findings may point to a new treatment strategy for preserving HSC function in patients undergoing chemotherapy.

Angiogenesis is induced in response to central nervous system (CNS) injury and inflammation. Toshihide Yamashita and colleagues show that in a mouse model of multiple sclerosis, new vessels form around inflammatory lesions and promote neuronal remodeling, rewiring of the corticospinal tract, and recovery of motor function in these mice. Prostacyclin is released from these vessels and promotes neuronal outgrowth by signaling through the IP receptor on neurons.

Human T cell function declines with age, reducing the ability of vaccines to protect the elderly against infectious disease. In this issue, Jörg Goronzy and his colleagues shed light on the mechanism by which naive CD4⁺ T cell responses are impaired in elderly individuals. The researchers show that miR-181a is reduced in these cells in older individuals. This results in increased expression of DUSP6, a phosphatase that dampens ERK signaling, which is necessary for optimal T cell receptor sensitivity to antigen.