Articles in 2013

A screen for compounds that may inhibit the growth of hematological malignancies reveals the specific dependence of some mantle cell lymphoma (MCL) cell lines on canonical or alternative NF-κB signaling. As also seen in patients, genetic alterations affecting alternative NF-κB signaling confer insensibility to ibrutinib, a compound that was recently approved for MCL treatment. This alternative signaling pathway underscores the need to tailor treatments to the specific driving pathways in each patient group.

After mosquito bite, the malaria parasite first infects the liver, where it is thought to be undetected by the host immune system as it develops into the blood-stage pathogen. Maria Mota and her colleagues now report that Plasmodium RNA is detected by hepatocytes, triggering an interferon response that controls the parasite burden in the liver and blood of infected mice.

Regulatory T (T_reg) cells exhibit substantial phenotypic and functional plasticity. Hiroshi Takayanagi and his colleagues report that in autoimmune arthritis, a subset of T_reg cells can lose Foxp3 expression and convert into T_H17 cells. This conversion is mediated by synovial fibroblast-derived IL-6, and in vivo, these cells are osteoclastogenic and exacerbate arthritis. These findings suggest that a proportion of pathogenic T_H17 cells in autoimmune disease may be derived from T_reg cells.

Understanding how Mycobacterium tuberculosis is controlled by the body, leading to active disease in only a small fraction of infected individuals, is important for developing medical interventions to prevent and manage disease. Lin et al. now show that infected macaques with active tuberculosis have some sterile granulomas, suggesting immune-mediated control at certain sites of infection. Insight into the mechanisms underlying the heterogeneity of mycobacterial killing may inform vaccine development.

Bao-Liang Song and colleagues report that the clathrin adaptor Numb recognizes a peptide motif within the cholesterol transporter NPC1L1 upon cholesterol binding and thus facilitates dietary cholesterol uptake into the gut. Inhibition of this Numb-NPC1L1 interaction in mice reduces serum cholesterol levels and thus may be a therapeutic target to treat hypercholesterolemia in the clinic.

The mechanisms underlying the association between obesity and the development of asthma remain incompletely understood. Dale T. Umetsu and his colleagues report that the number of IL-17A⁺ type 3 innate lymphoid cells (ILCs) is increased in the lungs of mice fed a high-fat diet. Activation of the NLRP3 inflammasome in lung macrophages promotes IL-1β production and ILC development, and blockade of IL-1 signaling inhibits airway hyperreactivity in obese mice. As these ILCs are also found in the lungs of individuals with asthma, these results suggest that this pathway may be targeted in asthma.

One of the most likely substrates for metabolic imaging of response to treatment in cancer is glucose, but until now, using hyperpolarized 13C-labelled glucose has been problematic because of the short lifetime of the hyperpolarization in this molecule. Using [U-¹³C, U-²H]glucose, Tiago Rodrigues et al. now show that they are able to image its glycolytic conversion to lactate in two mouse tumor models in vivo, and that in one model, flux is markedly reduced after treatment with the chemotherapeutic drug etoposide.

Nephrotic syndrome is marked by excess of both protein in the urine (proteinuria) and triglycerides in the blood (hypertriglyceridemia). Sumant Chugh and his colleagues now explain these linked pathologies while also suggesting a possible new therapy to treat the proteinuria without aggravating the hypertriglyceridemia.

The suppressive function and number of regulatory T cells (T_reg cells) is reduced in autoimmune disease. Here, Giuseppe Matarese and colleagues report that T_reg cell proliferation is reduced in subjects with relapsing-remitting multiple sclerosis. As disease severity increases, T_reg cell proliferation progressively decreases and is associated with impaired IL-2 release and IL-2 receptor and mTOR signaling.

There are currently a paucity of approaches for the direct in vivo assessment of rates of hepatic mitochondrial oxidation and anaplerotic flux in humans. With this in mind, Douglas Befroy and colleagues have developed a new ¹³C-labeling strategy that they use in combination with ¹³C magnetic resonance spectroscopy, which should prove useful in determining the potential role of changes in hepatic mitochondrial fat oxidation in diseases such as nonalcoholic fatty liver disease and type 2 diabetes.

Recurrent disease after apparent 'cure' of primary tumors is a common factor that contributes to cancer-associated mortality. A new study suggests that an inflammatory cytokine signature may provide a clinical indication of emergent recurrent disease and, accordingly, may suggest how to select and deliver therapy targeted against the secondary tumor (pages 1625–1631).