Research articles

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.

Cancer stem cells are thought to be resistant to anticancer therapies and are able to repopulate tumors and sustain tumor growth. The authors establish BMI-1 as a crucial regulator of cancer cell stemness in colorectal tumors and develop a chemical inhibitor that targets cancer stem cell renewal by reducing the levels of BMI-1. This strategy affords antitumor effects in vitro and in vivo and may pave the way for the precise targeting of elusive cancer stem cells.

Autoimmunity is triggered by trafficking of self-reactive T cells into tissues. Joonsoo Kang and colleagues show that the kinase ITK regulates T cell trafficking. ITK inhibition or genetic ablation prevents homing of autoreactive T cells into tissues and reduces islet destruction in models of type 1 diabetes without affecting T cell activation or antiviral T cell responses, suggesting that this kinase may be targeted in autoimmune disease.

T cells specific for hepatitis C virus (HCV) have been reported in some individuals who have been repeatedly exposed to virus, yet have never had detectable HCV or HCV-specific antibodies. These findings suggest that T cells in these individuals may protect against infection by HCV. Barbara Rehermann and colleagues now test this assumption in a nonhuman primate study exposing animals to a very low dose of HCV.

Matthias Hackl and his colleagues developed a new serial multiphoton microscopy approach to track migrating podocytes and parietal epithelial cells over time in vivo in the intact kidney. Use of this new approach is demonstrated in several mouse models and should help answer questions surrounding podocyte proliferation and migration to other (peri)glomerular regions, thus shedding light on the mechanisms of glomerular injury and regeneration.

Detecting tumor recurrences early and developing therapies capable of targeting recurrences that resist frontline therapy could be of enormous benefit to patients with cancer. Using mouse tumor models, Richard Vile and colleagues find a cytokine signature associated with very early stage recurrences, as well as evidence that the recurrent tumors are resistant to innate immune responses. By targeting the altered phenotype of the recurrent tumors, the researchers cured the mice of cancer, suggesting new avenues for research into human cancer recurrence.

Excess ammonia in the blood can cause neurologic dysfunction and seizures. Although previous studies have suggested astrocyte swelling and brain edema are associated with hyperammonemia, the authors show that ammonia compromises potassium buffering by astrocytes, increasing extracellular potassium concentrations and resulting in cortical disinhibition. Pharmacological or genetic inhibition of NKCC1 attenuates ammonia-induced neurologic impairment and seizures, suggesting hyperammonemia may be treated by targeting NKCC1.

Dean Sheppard and his colleagues show that genetic or pharmacological inhibition of α_v integrin signaling ameliorates fibrosis in several solid organs.

In exploring the possibility that racial differences in platelet function might exist, Paul Bray and his colleagues report that platelets from blacks have a greater propensity to aggregate than those from whites in response to activation of the PAR4 thrombin receptor. Mechanistically, this difference in platelet function seems to reflect differences in the expression of the microRNA miR-376c and its target, the enzyme phosphatidylcholine transfer protein.

Metformin is one of the most widely prescribed therapeutics for type 2 diabetes. But exactly how it works is still unclear. Gregory Steinberg and colleagues now show that it does so by activation of the enzyme AMP-activated protein kinase (Ampk) and Ampk's obligate targeting of two key enzymes involved in lipid homeostasis.

Variation in the promoter of the gene encoding uromodulin, the most abundant protein in urine, affects the individual risk of developing hypertension or chronic kidney disease. Luca Rampoldi, Olivier Devuyst and their colleagues show that the uromodulin risk alleles are associated with higher levels of uromodulin expression. This can promote hypertension, by stimulating sodium reabsorption by the loop of Henle in the kidney, and kidney damage in both mice and humans.