Research articles

Polly Matzinger and her colleagues have shown that in the absence of B cells, and in the presence of the microbiota, the intestinal epithelium launches its own immune defense mechanisms. However, this comes at the expense of metabolic programs involved in fat absorption by the gut. These results could explain the lipid malabsorption often seen in humans with common variable immunodeficiency or with HIV infection.

Glycoconjugate vaccines—such as those targeting some bacteria—couple a glycan to a protein to provide T cell help to B cells and induce polysaccharide-specific IgGs. T cell help has been thought to be conferred by recognition of the protein portion by T cells. Dennis Kasper and his colleagues now report that a glycan-peptide conjugate can induce T cells specific for the glycan moiety, which could help inform future glycoconjugate vaccine development.

This report identifies a new contribution of members of the miR-200 family to tumorigenesis. miR-200a and miR-141 specifically regulate p38α, contributing to the cellular modulation of oxidative stress responses. In this role, the miRs can accelerate ovarian tumorigenesis but also endow cancer cells with increased sensitivity to ROS-inducing chemotherapy. This two-part effect is reflected on the distinct association of the miRs with patient survival and may be informative for treatment decisions.

Although maturation of dendritic cells can drive autoimmune responses in mice, it remains unclear whether intrinsic factors hold dendritic cells in a resting state. Pamela Ohashi and her colleagues identify a repressive mechanism requiring expression of nuclear factor-κB1 in dendritic cells. Loss of nuclear factor-κB1 results in CD8⁺ T cell activation, TNF-α production and autoimmune diabetes in mice.

Raf kinase activity is deregulated in cancers and is thought to promote tumor growth by inducing proliferation signaling through MEK/Erk. This report identifies a new role for c-Raf independent of MEK/Erk and relying on phosphorylation of Ser338. Phospho–C-Raf interacts with the mitotic kinases Aurora-A and Plk1, activating the latter to promote mitotic progression and increase cell division, and this pathway is a crucial mediator for the protumorigenic effect of c-Raf in vivo.

The enzyme argininosuccinate lyase (ASL) generates the amino acid arginine, the precursor to both urea and nitric oxide. However, arginine supplementation is not sufficient to correct all of the symptoms of individuals with a congenital deficiency of this enzyme. Ayelet Erez et al. explain this paradox by showing that ASL has a role in nitric oxide synthesis that is independent of its catalytic activity and provide evidence that therapy with agents boosting nitric oxide levels might be beneficial in ASL-deficient individuals.

It is well regarded that insulin receptor signaling in the liver is key to proper metabolic control. Reza Zarnegar and his colleagues now show that the hepatocyte growth factor receptor, Met, physically interacts with the insulin receptor signaling complex, potentiating the latter's signaling. They also show that Met signaling restores insulin responsiveness in a mouse model of insulin resistance, suggesting a potentially new therapeutic avenue to treat prediabetes.

The hormone aldosterone can damage the heart after myocardial infarction, such that drugs that inhibit its action are often prescribed. B. Julie He et al. now uncover a new pathway underlying the detrimental effects of aldosterone action: oxidation of the enzyme Ca²⁺/calmodulin-dependent protein kinase II leads to its activation and increased expression of the metalloprotease MMP9 in cardiac muscle cells, thereby promoting cardiac rupture.

b-AP15 is a novel inhibitor of proteasome activity, with a different mechanism of action than the available and widely used proteasome inhibitors such as bortezomib. b-AP15 inhibits the deubiquitinating activity of the regulatory subunit of the proteasome, necessary for protein degradation, and induces cytotoxicity impairing tumor growth in mouse models. The compound may represent an alternative therapeutic approach with a broader spectrum of applicability than current proteasome inhibitors.

The future of imaging is the integration of function and anatomy. Hongki Yoo et al. have successfully done just that by combining two existing intravascular imaging techniques into a single catheter-based system. Their dual-modality intra-arterial catheter uses a combination of optical frequency domain imaging and near-infrared fluorescence imaging to simultaneously provide molecular information in the context of the surrounding three-dimensional microanatomy of the artery wall.

Makoto Mitsunaga et al. have developed a new form of molecular-targeted cancer therapy that provides an alternative to current photodynamic approaches where damage to surrounding healthy cells and tissues can be a problem. They use a target-specific photosensitizer based on a near-infrared phthalocyanine dye, which is conjugated to monoclonal antibodies targeting human epidermal growth factor receptors (HER1 and HER2). Selective treatment using this approach was shown in vivo in subcutaneous cancer xenografts in mice.

Osteoarthritis, the breakdown of cartilage in synovial joints, has long been viewed as the result of 'wear and tear', but this report shows that dysregulation of the complement system has an active role in the pathogenesis of this disease.

Ovarian tumors preferentially metastasize to the omentum, a peritoneal fat layer. This report proposes that the reasons for this predilection stem from the growth advantage conferred by adipocytes on ovarian cancer cells. Adipocytes seem to promote homing of cancer cells through adipokine secretion, and direct contact of the two cell types promotes metabolic changes that result in lipid transfer from adipocytes to tumor cells. Environmental-driven metabolic adaptations could be exploited to target omental metastasis.

Helga Ellingsgaard et al. show that secretion of interleukin-6 by muscle in response to exercise, or injection of recombinant protein, increases the expression of the incretin GLP-1 by both intestinal cells and by pancreatic alpha cells, thus potentiating insulin release and improving glycemic control. These results identify a new endocrine loop linking energy demands to homeostatic control while also suggesting further targets for type 2 diabetes therapy.

Fahumiya Samad and her colleagues have shown that the serine protease tissue factor, a key regulator of coagulation, has a role in obesity and metabolic disease. They find that tissue factor signaling in adipocytes promotes obesity, whereas its signaling in adipose tissue macrophages promotes local inflammation and insulin resistance.

By implementing the conditions for orthotopic implantation of different types of human breast tumors, the authors have created a publicly available bank of new mouse models that more faithfully recreate individual tumor properties and provide individualized information about tumor behavior and prognosis.

The holy grail in the bone field is the identification of a pharmacological compound that promotes bone growth during osteoporosis. Hiroshi Takayanagi and his colleagues take a step forward in that direction by showing that osteoclast-mediated expression of semaphorin D inhibits osteoblast differentiation and that, by inhibiting this pathway with a blocking antibody, they could prevent bone loss in a mouse model of osteoporosis.

Séverine Coulon et al. identify a new mechanism regulating red blood cell production through transferrin receptor engagement. By binding this receptor on erythroblasts, the polymeric form of immunoglobin A1 (pIgA1) or iron-loaded transferrin acts in conjunction with erythropoietin to promote erythroblast maturation. Administration of either pIgA1 or iron-loaded transferrin accelerated recovery from anemia in mice, suggesting that these findings may have therapeutic implications.

Spinocerebellar ataxia 1 is a neurodegenerative disease caused by a CAG trinucleotide expansion in the ATXN1 gene encoding the protein ataxin-1. Puneet Opal and his colleagues find that ataxin-1 represses the expression of the angiogenic and neurotrophic factor vascular endothelial growth factor (VEGF) and that VEGF levels are decreased in animals with motor impairment. Overexpression or infusion of VEGF improves motor performance and pathology, suggesting VEGF may have therapeutic potential in this disease.

Jan Brosens and his colleagues have found that deregulation of a single kinase—SGK1, a kinase involved in fluid balance—in two distinct cellular compartments of the endometrium is linked to two different forms of reproductive failure in humans. Using gain- and loss-of-function approaches in mice, the group confirmed the importance of these expression changes in such pathologies.