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'News From The Journal Of Clinical Investigation: June 11, 2012'
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ALLERGY AND ASTHMA
Evidence for a new therapeutic target for inflammatory skin diseases
Many chronic inflammatory diseases, including atopic dermatitis and asthma, are initially triggered by an allergic reaction. However, the mechanism through which an allergic reaction becomes a chronic condition remains poorly understood. A recent study from Kenji Izuhara and colleagues at the Saga Medical School in Japan investigated the role of periostin, which is a protein involved in tissue development, in a mouse model of allergic inflammation. The team found that following exposure to a known allergen, periostin accumulated in the ear tissue and skin cells of mice and then interacted with a signaling protein called alphav to stimulate chronic inflammation. They also showed that mice lacking periostin or alphav were resistant to allergic skin inflammation compared to control mice. This study reveals that periostin plays an important role in the development of chronic skin inflammation following allergen exposure and identifies periostin as a potential therapeutic target for allergic skin diseases in humans.
TITLE: Periostin promotes chronic allergic inflammation in response to Th2 cytokines
IMMUNOLOGY
Tolerating transplantation
Organ transplantation has saved millions of lives. One of the most critical components to a successful transplant is minimizing the recipient patients immune response to the foreign organ. The use of immunosuppressive drugs has been critical for allowing tolerance of the transplanted organ. Dr. Terry Strom and colleagues at the Harvard Medical School wanted to better understand the specialized immune cells known as regulatory T cells that infiltrate the transplanted organ and play an important role in tolerating the transplant. They identified a population of regulatory T cells in mice that rapidly and robustly infiltrate the transplanted skin grafts. These specialized cells, which express the T cell Immunoglobulin and Mucin domain-3 protein (TIM-3) on their surface, are short-lived and their levels peak at the time of graft rejection. Their results suggest that TIM-3+ regulatory T cells are an important mediator of graft rejection in mice.
TITLE: Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs
PULMONARY BIOLOGY
Insights into the mechanisms of acute lung injury
About 200,000 US citizens develop and 80,000 die every year from acute lung injury. A major cause of acute lung injury is blood transfusion, also known as transfusion-related acute lung injury (TRALI). Acute inflammation and injury in TRALI appear to be dependent on blood platelets sequestered in the lung microcirculation in a process dependent on immune cells known as neutrophils, but the molecular mechanisms are unknown. A research team lead by Mark Looney from the University of California at San Francisco has focused on neutrophil extracellular traps (NETs) to explain the neutrophil and platelet-dependent lung damage observed in TRALI. NETs are extracellular traps to pathogens formed by proteins and DNA filaments released from dead neutrophils. Dr. Looney's team discovered NETs in the lungs and plasma of TRALI patients and in the plasma of patients with acute lung injury. Using a TRALI mouse model, the researchers demonstrated that preventing platelet activation with aspirin reduces NET formation. Moreover, mice were protected from TRALI by targeting NET components by treatment with a blocking antibody or DNaseI, an enzyme that cleaves DNA. This study demonstrates that NETs contribute to lung endothelial injury, and that disrupting NET formation is an attractive target for the treatment of acute lung injury.
METABOLISM
Thyroid hormone stimulates lipid breakdown
For more than a century, thyroid hormones (THs) have been known to exert powerful catabolic effects leading to weight loss. Although much has been learned about the molecular mechanisms used by TH receptors (TRs) to regulate gene expression, little is known about the mechanisms by which THs increase oxidative metabolism. Dr. Paul Yen and colleagues at the Duke-NUS Medical School in Singapore report that TH stimulation of fatty acid ß-oxidation is coupled with induction of hepatic autophagy to deliver fatty acids to mitochondria in cell culture and in vivo. Furthermore, their results demonstrate that THs can regulate lipid homeostasis via autophagy and help to explain how THs increase oxidative metabolism.
TITLE: Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy
OPHTHALMOLOGY
Development of vision impairment in central serous chorioretinopathy
Central serous chorioretinopathy (CSCR) is a vision-threatening eye disease with no validated treatment and unknown pathogeny. Subretinal fluid accumulation originates from dilation and leakage of choroid vessels underneath the retina. Because glucocorticoids induce and aggravate CSCR and can occupy the mineralocorticoid receptor (MR), CSCR may depend on inappropriate MR activation. Dr. Nicolette Farman and colleagues at INSERM in Paris, France report on the effect of MR activation on rat choroidal vasculature and to transfer results for patients with CSCR. Their results identify MR signaling as a novel pathway controlling choroidal vascular bed relaxation and provide a pathogenic link with human CSCR, leading to proposal of short-term MR blockade to reverse the choroid vasculopathy.
TITLE: Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy
ONCOLOGY
New mediator of prostate cancer identified
Cell proliferation requires a chain of signaling events that begins with extracellular ligands and ends with alterations in nuclear gene expression. In prostate cancer, these signals change with time, as tumors progress from castration-sensitive (androgen-dominant) to castration-resistant states. While the mechanisms underlying this change remain uncertain, effective prostate cancer treatment will involve characterization of common signaling components that regulate both stages of prostate cancer proliferation. Dr. Stephen Hammes and colleagues at the University of Rochester Medical center report that that paxillin, a known cytoplasmic adaptor protein, regulates both androgen- and epidermal growth factor (EGF)-induced nuclear signaling. Their findings indicated that paxillin is a liaison between extranuclear MAPK signaling and nuclear transcription in response to androgens and growth factors, making it a potential regulator of both castration-sensitive and castration-resistant prostate cancer.
TITLE: Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation
ONCOLOGY
DNA repair is required for cancer survival in mice with acute inflammation
Underlying infections or inflammatory conditions are associated with more than 15% of world-wide cancer deaths. Inflamed tissues are known to harbor elevated DNA damage lesions induced by reactive oxygen and nitrogen species from activated immune system cells such as neutrophils and macrophages. Understanding how inflammation contributes to cancer etiology is important for both cancer prevention and treatment. Using an established mouse model of colon cancer initiation combined with inflammatory stimuli, Leona Samson and colleagues at MIT in Cambridge, Massachusetts show that the DNA repair enzymes ALKBH2 and ALKBH3 provide critical cancer protection.
TITLE: DNA repair is indispensable for survival after acute inflammation in mice
METABOLISM
Molecular regulators of lipid homeostasis
Insulin is the primary stimulator of hepatic lipid production. Dr. Fajun Yang and colleagues at the Albert Einstein College of Medicine in the Bronx, NY identify cyclin-dependent kinase 8 (CDK8) and its regulatory partner Cyclin C (CycC) as negative regulators of the lipogenic pathway in Drosophila, mammalian hepatocytes and mouse livers. Their results demonstrate that CDK8 and CycC function as novel and conserved components of the insulin signaling pathway in regulating lipid homeostasis.
TITLE: Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1
