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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 (Treg) cells exhibit substantial phenotypic and functional plasticity. Hiroshi Takayanagi and his colleagues report that in autoimmune arthritis, a subset of Treg cells can lose Foxp3 expression and convert into TH17 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 TH17 cells in autoimmune disease may be derived from Treg cells.
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.
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.
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.
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.
Dean Sheppard and his colleagues show that genetic or pharmacological inhibition of αv 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.
The kinase Mst1, which acts in the Hippo pathway, controls cell proliferation, differentiation and apoptosis. Junichi Sadoshima and his colleagues show that Mst1 in cardiomyocytes phosphorylates the protein Beclin1 to coordinately suppress autophagy and promote apoptosis, thereby having deleterious effects on the heart.
Diabetic nephropathy is the most common cause of end-stage renal disease. Shu Wakino and colleagues now show that high-glucose conditions in the renal proximal tubules result in downregulation of Sirt1 expression there and in the glomeruli, resulting in epigentic upregulation of Claudin-1 in the glomeruli and thus proteinuria. They also show that genetic or chemical targeting of Sirt1 in the kidney is sufficient to improve kidney function in a mouse model of diabetic nephropathy.
Cellular stress results in the release of damage-associated molecular pattern (DAMP) molecules that promote inflammatory responses. Here Ping Wang and colleagues show that cold-inducible RNA-binding protein (CIRP) is a DAMP that is released into the circulation in response to hemorrhagic shock and sepsis. It promotes proinflammatory cytokine release by binding to the TLR4-MD2 complex. Blockade of CIRP reduces inflammation, organ injury and mortality in animal models of hemorrhage and sepsis, suggesting that CIRP may be targeted therapeutically in these conditions.
In a new study, Yingzi Yang and her colleagues show that a careful balance between Wnt and Hedgehog signaling is required to maintain proper differentiation of osteogenic precursor cells. Upon mutation of GNAS, this balance is disturbed and severe bone disease develops, including either heterotopic ossification or fibrous dysplasia.
The authors provide preclinical testing of a CSFR-1 inhibitor in proneural glioma models. The compound targets macrophages in the tumor microenvironment rather than tumor cells themselves and is shown to portend considerable antitumor effects. Its activity relies on re-education of tumor-associated macrophages without affecting their survival, reverting their tumor-promoting phenotype. Moreover, gene signatures capturing the tumorigenic features of macrophages can predict survival in human patients with glioma, underscoring the potential relevance of this strategy as a glioma therapy.
In the process of autophagy, cellular constituents are degraded and recycled. Toren Finkel and his colleagues show that this process also regulates the secretion of a key blood-clotting protein by endothelial cells, such that transient inhibition of autophagy might be therapeutically useful for treating thrombotic disorders.
The correlates of protection against illness caused by natural influenza infection in seronegative individuals is important for the design of vaccines capable of conferring immunity against different influenza virus strains. Sridhar et al. now report their analysis of individuals infected by the 2009 H1N1 pandemic influenza virus and show that the presence of pre-existing CD8+ T cell responses to conserved influenza epitopes is associated with reduced severity of illness. The findings support the importance of developing universal influenza vaccines that are capable of inducing crossreactive T cell responses to mitigate influenza illness.
Rapamycin (also known as sirolimus) is a potent immunosuppressive drug that is often used after organ transplant to prevent rejection, but it also can cause kidney dysfunction. Fabiola Terzi and her colleagues now show this side effect of rapamycin is due to targeting of mTORC2 and suppression of AKT2 activity in podocytes. They also show that AKT2 normally acts to maintain podocyte viability and structure during chronic kidney disease.
After myocardial infarction, inflammatory cells are rapidly recruited to the heart and strongly affect the course of recovery. Ziad Mallat and his colleagues uncover a pathogenic role for B cells after myocardial infarction, showing that infarction triggers B cell secretion of the chemokine Ccl7, which mobilizes monocytes from the bone marrow, increases their recruitment to the heart and impairs heart function.
Sensitization to the fungus Aspergillus fumigatus is associated with allergic airway disease and asthma. Now Dale Umetsu and colleagues report that invariant natural killer T (iNKT) cells directly recognize the glycosphingolipid asperamide B derived from A. fumigatus. Asperamide B stains and activates mouse and human iNKT cells and induces airway hyper-reactivity in mice, suggesting that fungi can be directly detected by iNKT cells.
α-secretase–mediated processing of cellular prion protein and amyloid precursor protein is decreased in prion and Alzheimer's diseases. Mathéa Pietri et al. now show that activity of a kinase, PDK1, is increased in the brain following prion infection and with amyloid pathology. This results in internalization of TACE and impairs TACE-mediated α-secretase activity. Inhibition of PDK1 is beneficial in mouse models of prion infection and Alzheimer's disease, suggesting PDK1 may be targeted to attenuate disease progression.
