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Experiments in two mouse models of thromboinflammatory disease show how neutrophils stick to red blood cells and platelets—leading to reduced blood flow and damage to the microcirculation. Polarized expression of αMβ2 integrins on neutrophils helps set the process in motion (pages 384–391).
Toll-like receptors on lung epithelia recognize allergens and help provoke asthma. The findings put new emphasis on innate immunity as a driver of allergic responses (pages 410–416).
An indigestion drug blamed for a debilitating illness that affected thousands of people in the 1950s has been resurrected as a potential treatment for Alzheimer's disease. But not everyone is cheering for the drug, clioquinol, to make a comeback. Lauren Cahoon reports.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome that is often difficult to treat. Hiroshi Watanabe and coworkers now show that flecainide, an approved drug known to inhibit sodium channels, is able to target the underlying cause of CPVT by inhibiting calcium release through the ryanodine receptor. Flecainide prevented arrhythmia in a mouse model of CPVT and was also effective when tested in two individuals with CPVT.
Granulocyte colony-stimulating factor (G-CSF) is used to accelerate neutrophil engraftment in bone marrow transplant (BMT) recipients to reduce bacterial infections but may also enhance the risk of graft-versus-host disease (GVHD). Morris et al. now show that total body irradiation increases the expression of the G-CSF receptor on recipient dendritic cells, resulting in the activation of donor natural killer T cells and enhanced GVHD when G-CSF is administered shortly after BMT (pages 363–364).
Kurt Redlich and his colleagues show that estrogen deficiency results in increased numbers of preosteoclast progenitor cells in the bones of mice. But they also find that lack of CCR2 in these future bone-resorbing cells prevents their maturation and thus protects the mice from osteoporosis, suggesting a future target for therapy in humans.
House dust mite allergen (HDM) is a potent trigger of airway inflammation. Dendritic cells (DCs) and lung epithelial cells both express the pathogen receptor TLR4, which senses lipopolysaccharide contaminating the allergen. Bart Lambrecht and his colleagues show that TLR4 on the epithelial cells, not the DCs, is the primary sensor of HDM. TLR4 on these lung structural cells is required for recruitment of DCs and the induction of allergic inflammation in response to HDM (pages 366–367).
Inhibitors of αvβ3 and αvβ5 integrins have previously been shown to inhibit tumor angiogenesis and growth and have entered human clinical trials. Andrew Reynolds and his coworkers now show that low (nanomolar) concentrations of these inhibitors can unexpectedly promote VEGF-dependent tumor angiogenesis and growth in vivo. Such effects could compromise the anticancer efficacy of these agents in humans.
Signaling between endothelial and blood cell types controls inflammatory and thrombotic responses. Andrés Hidalgo and his coworkers now uncover a signaling mechanism by which the endothelium, acting on adherent leukocytes, promotes the capture of platelets or red blood cells by those leukocytes, contributing to pathology in mouse models of two very different types of disease—transfusion-related acute lung injury and sickle cell disease(pages 364–366).
The leukocyte enzyme myeloperoxidase (MPO) is key to normal host defense mechanisms. Dysregulated MPO, however, is linked to acute and chronic inflammatory conditions, such as atherosclerosis and cancer. The authors describe a luminol-based bioluminescence imaging system that provides an optical readout of physiological levels of MPO activity in vivo. The system is demonstrated in animal models of acute dermatitis, focal arthritis and spontaneous large granular lymphocytic tumors.
One way to reduce obesity is to alter fat absorption from the diet. Here Robert Farese, Jr. and his colleagues identify MGAT2 as a potential therapeutic target for doing so. The enzyme is mostly expressed in the gut of humans and mice, and its genetic deletion in mice results in slower kinetics of fat absorption—more of the fat is burned and less is stored, offering protection from diet-induced obesity.
The neurotoxic Aβ peptide is produced after traumatic brain injury. Mark P. Burns and his colleagues show that inhibiting the enzymes involved in Aβ production can block the neuron death and neurological dysfunction that occurs after traumatic brain injury.
Viral-mediated gene therapy presents many challenges in the clinic, including the potential for physiological effects that overshoot the intended goals. In a new report by Matthew During and his colleagues, the authors devise a scheme by which packaging of a microRNA into the virus, expressed under the control of a physiological response induced by the viral transgene, allows coordinated dampening of the transgene expression when the therapeutic response achieves a certain threshold.
New factors in wound healing are sorely needed. Here Youngsook Son and colleagues identify substance P, a small neuropeptide, as one such factor that seems to work by mobilizing stromal-like cells to the site of wounding, accelerating the healing process (pages 367–369).