Articles in 2012

Yuji Okuno et al. find that pathological angiogenesis in mice requires dampening of oxidative stress. In the absence of the ATM protein kinase, increased oxidative stress leads to activation of the p38α protein kinase and inhibition of new blood vessel growth. These findings run counter to the commonly held concept that decreasing oxidative stress would inhibit pathological angiogenesis and suggest new targets for treating diseases involving abnormal blood vessel growth.

Febrile seizures during childhood are linked to the development of chronic epilepsy. Now, Ryuta Koyama and colleagues show that febrile seizures are associated with enhanced GABAergic excitation and ectopic granule cell migration in the hippocampus.

In this issue, Thomas Kupper and colleagues report that mice deficient for ROR-γ or interleukin-23 (IL-23) receptor showed impaired melanoma growth. Tumor growth inhibition was dependent in part on IL-9 and T helper type 9 (T_H9) cells. Moreover, the authors showed that IL-9 acts on mast cells rather than T or B cells to mediate its antitumor effects and that T_H9 cells are present in human blood and skin, suggesting that a role for T_H9 cells in human tumor immunity should be explored.

Spondyloarthropathies are characterized by a distinct pattern of inflammation at distinct anatomical sites and are associated with elevated expression of interleukin 23 (IL-23). Daniel Cua and his colleagues identify an IL-23–responsive CD4⁻CD8⁻ T cell population located within entheses. Systemic overexpression of IL-23 activates these cells and recapitulates aspects of the human disease in mice, and neutralization of IL-17 and IL-22 decreases pathology, suggesting new therapeutic targets for these disorders.

Bone remodeling involves a coupled balance between bone resorption and bone formation. Xu Cao and his colleagues have shown before that mesenchymal stem cells (MSCs) are recruited to the surface of the bone during this process. They now show that insulin-like growth factor 1 (IGF-1) is released from the bone surface during bone resorption, where it signals the recruited MSCs to differentiate into osteoblasts. In this way, bone resorption is linked to bone formation, and IGF-1 as a target of bone therapy is suggested.

Hepatitis B virus (HBV) infection is known to be controlled by T and B cell responses, but the role of natural killer T (NKT) cells is less clear. Richard Blumberg and his colleagues now show that NKT cells are activated immediately after HBV infection by presentation of an HBV-altered repertoire of lysophospholipids on infected hepatocytes and are necessary for the induction of optimal T and B cell responses and rapid viral control.

By digital profiling of residual breast tumors after neoadjuvant therapy, the authors identify gene expression patterns that correspond with a higher risk of metastasis and recurrence. Activation of the Ras-ERK pathway through loss of DUSP4 confers therapy resistance that can be overcome by combined treatment with MEK inhibitors.

Temporal lobe epilepsy (TLE) is linked to neuron death in the hippocampus. Now David Henshall and colleagues show that miR-134 is upregulated in humans with TLE and in an experimental epilepsy model in mice. Decreasing miR-134 before induction of epilepsy in mice reduces neuron death and the generation of spontaneous seizures.

Several microRNAs have been identified that affect lymphocyte effector function and contribute to autoimmune inflammatory disease. Here Youcun Qian and his colleagues find that interleukin-17 (IL-17) suppresses miR-23b expression in nonimmune cells present in inflammatory lesions from individuals with rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis and in the respective mouse models. MiR-23b targets several signaling molecules downstream of IL-17, TNF-α and IL-1β signaling, thereby suppressing proinflammatory cytokine expression and inhibitng autoimmune pathogenesis in vivo.

Endometriosis afflicts ~15% of women of reproductive age, causing pelvic pain, and is often associated with infertility. In a new study, Bert O'Malley and his colleagues now show that in response to TNF-α signaling, a unique isoform of SRC-1, an estrogen receptor coactivator, is elevated in endometriotic tissue, preventing the normal apoptosis of these cells. These results could explain the proliferation of these cells, while also further suggesting the antibody to TNF-α etanercept as a therapy for this condition.

Exosomes can transfer proteins and nucleic acids from one cell to another, altering the phenotype of the recipient cell. In the case of cancer, tumor-derived exosomes have been shown to promote tumor cell proliferation. Now, in a mouse model of melanoma, Peinado et al. report that exosomes derived from highly metastatic tumor cells can influence bone marrow cells, resulting in increased recruitment of provasculogenic bone marrow progenitors to sites of metastasis, increased primary tumor growth and metastatic spread.

The crosstalk between the transcriptional activity of β-catenin and FOXO3a reveals unexpected pro-metastatic cooperative effects of these pathways through concurrent modulation of cell adhesion and motility programs. In tumors with high FOXO3a and β-catenin activity, the proapoptotic effect of FOXO3a is subverted and the pro-proliferative effect of β-catenin is also dampened, but pro-metastatic pathways are activated. These findings suggest that caution should be exerted when using targeted inhibitors that activate FOXO3a in tumors with high β-catenin activity, as coactivation of both pathways also correlates with more aggressive disease in humans.

Brain cells that die after stroke release intracellular proteins into their environment. Akihiko Yoshimura and his colleagues demonstrate that peroxiredoxin proteins released from dying cells induce inflammatory cytokine expression and drive brain damage after stroke.

Glucose and its metabolic derivatives are increased the plasma of patients with diabetes. Peter Nawroth and colleagues demonstrate that one such metabolite, methylglyoxal, is increased in patients with painful diabetic neuropathy, and find that it acts by modifying the excitability characteristics of a sodium channel protein.

Hepatic glucose production is elevated in obesity and type 2 diabetes, contributing to the hyperglycemia that occurs in these conditions. In a new study, Liangyou Rui and colleagues show that NF-κB–inducing kinase (NIK) is abnormally activated in states of obesity, resulting in elevated hepatic glucose production. When they inhibit NIK activity in the liver, hyperglycemia is lowered, suggesting NIK as a potential therapeutic target in the management of type 2 diabetes.

It is believed that lipid accumulation in the liver, or fatty liver disease, contributes to insulin resistance in this organ and, thus, poorly controlled gluconeogenesis and hyperglycemia during type 2 diabetes. Mitch Lazar and colleagues now show that deletion of the chromatin modifier Hdac3 in mice results in increased fatty liver disease but improved hepatic insulin sensitivity because metabolic flux in the liver is increased toward lipid synthesis and storage and away from gluconeogenesis.

Cigarette smoking raises the risk for cardiovascular disease, including the risk for abdominal aortic aneurysm. Shuangxi Wang et al. now show that nicotine itself is a causal factor in promoting abdominal aortic aneurysms in mice and delineate a pathogenic mechanism by which nicotine exposure leads to activation of the enzyme AMP-kinase in vascular smooth muscle cells and increased expression of the metallopeptidase MMP2.

Retinoids and their precursors are known to regulate adipose tissue maturation. Jorge Plutzky and his colleagues now show that an increased endogenous level of retinaldehyde in white adipose tissue, generated by genetic deletion of Raldh1, promotes its 'beiging' in a retinoic acid receptor–dependent manner. They also showed that genetic knockdown of Raldh1 and conversion of white to brown fat leads to weight loss and heightened glucose tolerance in obese mice in a therapeutic manner.

Interleukin-25 (IL-25) is released from lung epithelial cells in response to allergen challenge and promotes type 2 immune responses and allergic airway inflammation. Nicholas Lukacs and his colleagues now report that IL-25 acts on a myeloid population in the lung. These cells represent a major source of IL-4 and IL-13, promote allergic lung inflammation and are steroid resistant. The frequency of IL-4– and IL-13–producing myeloid cells is increased in individuals with asthma, suggesting these cells may have a crucial role in the development of asthma.

The maintenance of a normal intestinal microbiota is associated with gut integrity and healthy immune responses. In this issue, Janelle Ayres and her colleagues report that disruption of the gut microbiome with antibiotics, coupled with gut injury, leads to the outgrowth of a pathogenic commensal bacterium and a sepsis-like disease. Their results show that the Naip5-Nlrc4 inflammasome is crucial for sensing the pathobiont and is a key factor in triggering the disease phenotype.