Articles in 2013

George Kunos and his colleagues show in a rat model that endocannabinoid activation of the Nlrp3 inflammasome in macrophages results in death of pancreatic beta cells, and thus development of type 2 diabetes mellitus. These results suggest that preventing this process might be a therapeutic option for diabetes in the clinic.

The efficacy of anti-angiogenic therapy for cancer could be improved if tumor resistance mechanisms were better understood. In this report, Napoleone Ferrara and his colleagues uncover a tumor resistance mechanism to VEGF-neutralizing antibodies triggered by IL-17, the hallmark cytokine of T_H17 cells.

Eosinophilic esophagitis (EoE) is characterized by esophageal eosinophilia, but the underlying mechanisms promoting eosinophil accumulation remain unclear. David Artis and his colleagues describe a new mouse model of EoE-like disease. The development of EoE-like disease is dependent on thymic stromal lymphopoietin (TSLP) and basophils, whereas inhibition of TSLP or depletion of basophils attenuates established disease. Moreover, individuals with EoE have increased TSLP expression and basophils in the esophagus, suggesting that the TSLP-basophil axis can be targeted in patients with EoE.

Huntington's disease is a neurodegenerative disorder associated with glutamate receptor dysfunction. Now Isabel Pérez-Otaño and colleagues report that the HTT protein that aggregates in the brains of individuals with the disease disrupts the ability of the adaptor protein PACSIN1 to keep the glutamate receptor subunit GluN3A away from the surface of neurons.

Bart Staels and his colleagues show that the transcription factor Rev-erb-α is highly expressed in oxidative muscle and, via loss- and gain-of-function experiments, including pharmacological activation, that it plays a key partin regulating the oxidative capacity of the muscle and exercise endurance.

During B cell development, cells that fail to productively rearrange their immunoglobulin VH-DJH gene segments to generate an in-frame junction that codes for a functional pre-B cell receptor are deleted. Markus Müschen and colleagues now report that Bach2 is a key component of this pre-B cell receptor checkpoint that enables the elimination of normal and transformed B cells with nonfunctional V(D)J rearrangements by regulating the expression of p53.

Hepatic insulin resistance, a hallmark of type 2 diabetes, results in elevated blood sugar concentrations and fatty liver disease. Domenico Accili and his colleagues now show that inhibition of Notch signaling in the liver dampens the pathways leading to both conditions, thus improving these aspects of diabetes.

Studies on a new conditional mouse model reveal that ETS transcription factors, which are often mutated in prostate cancer, cause transformation by altering the androgen-receptor cistrome, priming the prostate epithelium to respond to upstream signals such as PTEN loss.

Myofibroblasts are associated with organ fibrosis, but their origin and functional role remain unknown. Using multiple genetically engineered mice, the authors found that in the kidney, myofibroblasts arise from multiple sources—resident fibroblasts, bone marrow, endothelial cells and epithelial cells. Targeting these different populations may therefore be required to inhibit the accumulation of myofibroblasts in kidney fibrosis.

Branched-chain amino acid transaminase 1, the enzyme that initiates the catabolism of branched-chain amino acids, is involved in glioma pathogenesis, making it a potential therapeutic target.

Activation of inflammasomes has been implicated in sensing pathogens. Now Dario Zamboni and colleagues report that the Nlrp3 inflammasome has a key role in restricting replication of Leishmania parasites in macrophages and in mice by triggering interleukin-1A–dependent induction of nitric oxide, a crucial mediator of defense against Leishmania.

This study identifies miR-30c as a regulator of both microsomal triglyceride transfer protein, needed for the secretion of APOB-containing lipoproteins such as low-density lipoproteins, and a number of other genes involved in lipid biosynthesis. In mice, miR-30c regulates hepatic lipid biosynthesis and lipoprotein secretion such that hepatic overexpression of miR-30c reduces plasma cholesterol and triglyceride concentrations and decreases atherosclerotic plaque burden.

Humans lack robust regeneration of hair follicles after skin wounding. George Cotsarelis and colleagues now show that γδ T cells are not present at high levels in human skin, that in mice they are a key initial source of the protein fibroblast growth factor 9 and that this factor modulates hair follicle regeneration during skin wound healing. These results suggest a possible topical clinical treatment to regrow hair after wounding and perhaps for other conditions of hair loss.

Monocytes play an important part in the clearance of pathogens during infection. Yasmine Belkaid and her colleagues now report that inflammatory monocytes can also have a regulatory role. Specifically, these cells can mitigate the tissue damage induced by neutrophils during infection of mice with Toxoplasma gondii by releasing prostaglandin E2 in response to commensal bacteria.

Lipid droplets have a key role in the assembly of hepatitis C virus (HCV) particles in liver cells. Jake Liang and colleagues now report that a host factor, IκB kinase-α is required for efficient production of HCV by increasing cellular lipid droplet content through its regulation of lipogenic genes in infected cells. The findings provide insight into some of the metabolic changes induced by HCV infection and may offer a new potential therapeutic target.

Pierre Guermonprez and colleagues have worked out how a subset of dendritic cells expands in individuals with severe malaria. Plasmodium infection causes an accumulation of xanthine in infected red blood cells. The researchers found that type I interferon triggers an increase in the enzyme that metabolizes xanthine to uric acid. Uric acid then acts on mast cells to release Flt3 ligand, an important regulator of dendritic cells, which in turn stimulate T cells to respond to the infection.

Osteoarthritis has been believed to be caused by improper mechanical function of articular joints. Xu Cao and his colleagues now show that this mechanical process leads to upregulation of transforming growth factor β1 activity in mesenchymal stem cells of subchondral bone, resulting in aberrant bone formation, further destabilization of the joint and ultimately the onset of the disease.

Many chemotherapy drugs cause sensory nerve damage as well as long-lasting damage to hematopoietic regeneration in the bone marrow. Paul Frenette and his colleagues show that this hematopoietic damage is caused by injury to bone marrow sympathetic nerve fibers, disrupting the hematopoietic stem cell niche. These findings point to the potential of neuroprotective agents in preserving hematopoietic function in chemotherapy-treated patients with cancer.

Type 1 regulatory (Tr1) T cells are characterized by their immunosuppressive activity and cytokine secretion profile; however, their isolation and enumeration are limited by the absence of specific markers. Here Richard Flavell, Maria-Grazia Roncarolo and colleagues report that CD49b and LAG-3 are coexpressed by human and mouse Tr1 cells. These markers can be used to isolate Tr1 cells in vitro and in vivo and can be used to quantify Tr1 cells in tolerant subjects.

Microglia are activated in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Here Shao-Cong Sun and colleagues demonstrate that the E3 ubiquitin ligase Peli1 is expressed in microglia and is required for their activation and expression of inflammatory cytokines and chemokines after the induction of EAE. Disease severity is reduced in Peli1-deficient mice, partly through the effects of Peli1 on TLR signaling and Traf3 degradation.