In this issue of the JCI, a study by Cauwels and colleagues suggests a central role for eNOS, the endothelial isoform of nitric oxide synthase, as a mediator of anaphylaxis (see the related article beginning on page 2244). Why is an enzyme originally described as a physiological mediator of vascular homeostasis implicated in the spectacular vascular collapse that is characteristic of anaphylaxis? And is the eNOS involved in anaphylaxis necessarily exerting its effect solely in the vascular endothelium, or might this “endothelial enzyme” actually be playing a more fundamental role in an entirely different tissue? After all, what’s in a name?
Charles J. Lowenstein, Thomas Michel
Anandamide (N-arachidonoylethanolamide) is a lipid signal molecule that was the first endogenous agonist for cannabinoid receptors to be discovered. Cannabinoid receptor type 1 (CB1) is widely distributed in neurons and nonneuronal cells in brain and peripheral organs including sperm, eggs, and preimplantation embryos. A study by Wang and colleagues in this issue of the JCI demonstrates that a critical balance between anandamide synthesis by N-acylphosphatidylethanolamine–selective phospholipase D (NAPE-PLD) and its degradation by fatty acid amide hydrolase (FAAH) in mouse embryos and oviducts creates locally an appropriate “anandamide tone” required for normal embryo development, oviductal transport, implantation, and pregnancy (see the related article beginning on page 2122). Adverse effects of elevated levels of anandamide on these processes resulting from FAAH inactivation are mimicked by administration of (-)-Δ9-tetrahydrocannabinol (THC; the major psychoactive constituent of marijuana), due to enhanced signaling via CB1. These findings show that exogenous THC can swamp endogenous anandamide signaling systems, thereby affecting multiple physiological processes.
Herbert Schuel
Psoriasis is a chronic inflammatory skin disease unique to humans. In this issue of the JCI, 2 studies of very different mouse models of psoriasis both report that macrophages play a key role in inducing psoriasis-like skin disease. Psoriasis is clearly a polygenic, inherited disease of uncontrolled cutaneous inflammation. The debate that currently rages in the field is whether psoriasis is a disease of autoreactive T cells or whether it reflects an intrinsic defect within the skin — or both. However, these questions have proven difficult to dissect using molecular genetic tools. In the current studies, the authors have used 2 different animal models to address the role of macrophages in disease pathogenesis: Wang et al. use a mouse model in which inflammation is T cell dependent, whereas the model used by Stratis et al. is T cell independent (see the related articles beginning on pages 2105 and 2094, respectively). Strikingly, both groups report an important contribution by macrophages, implying that macrophages can contribute to both epithelial-based and T cell–mediated pathways of inflammation.
Rachael A. Clark, Thomas S. Kupper
AIDS is characterized by CD4+ T lymphocyte depletion, yet the mechanisms underlying this central aspect of HIV pathogenesis are still poorly understood. In this issue of the JCI, Espert et al. identify a mechanism by which the HIV envelope glycoprotein can induce death in uninfected CD4+ T cells (see the related article beginning on page 2161). The HIV envelope glycoprotein interacts with CXC chemokine receptor 4 to activate the lysosomal degradation pathway of autophagy, which is necessary for both apoptotic and nonapoptotic cell death.
Beth Levine, Donald L. Sodora
Negative or inhibitory costimulatory pathways regulate T cell activation and play a role in peripheral tolerance. Targeting these pathways harnesses the physiologic mechanisms of regulating autoimmunity and could prove beneficial for the therapy of autoimmune diseases. However, attempts at targeting these pathways have been fraught with difficulties. In this issue of the JCI, Fife et al. describe a creative approach for targeting CTL-associated antigen 4 (CTLA-4) on activated T cells via genetically engineered B cells to prevent autoimmune diabetes in the NOD mouse (see the related article beginning on page 2252). Novel “designer” strategies targeting negative costimulatory pathways provide reasons for optimism in the search for a cure for devastating autoimmune diseases.
Mohammed Javeed Ansari, Mohamed H. Sayegh
The glomerular capillaries function as the filtration barrier that retains albumin and other plasma proteins in the circulation. The unresolved question that has been asked for more than 50 years is, Which structural component of these capillaries constitutes the main molecular sieve that normally retains albumin and allows its passage in diseases associated with proteinuria? There is considerable evidence implicating both the glomerular basement membrane (GBM) and the epithelial filtration slits as the barrier. However, the prevailing point of view at present is that the slit diaphragms bridging the filtration slits are responsible for this important function, and evidence implicating the GBM is largely ignored or forgotten. In this issue of the JCI, Jarad et al. show that in laminin β2–deficient (Lamb2–/–) mice, proteinuria can be directly attributed to the altered composition of the GBM (see the related article beginning on page 2272). Changes in the permeability of the GBM and its organization were primary to changes in the epithelium, as they preceded foot process effacement and loss of slit diaphragms.
Marilyn G. Farquhar
Several clinical trials of bone marrow stem cell therapy for myocardial infarction are ongoing, but the mechanistic basis for any potential therapeutic effect is currently unclear. A growing body of evidence suggests that the potential improvement in cardiac function is largely independent of cardiac muscle regeneration. A study by Fazel et al. in this issue of the JCI provides evidence that bone marrow–derived c-kit+ cells can lead to an improvement in cardiac function in mutant hypomorphic c-kit mice that is independent of transdifferentiation into either cardiac muscle or endothelial cells, but rather is associated with the release of angiogenic cytokines and associated neovascularization in the infarct border zone (see the related article beginning on page 1865). These findings suggest the potential therapeutic effect of specific paracrine pathways for angiogenesis in improving cardiac function in the injured heart.
Kenneth R. Chien
Adenosine, long known as a regulator of cardiovascular function, has recently been identified as a significant paracrine inhibitor of inflammation that acts primarily by activation of A2A adenosine receptors (A2AARs) on lymphoid or myeloid cells. In this issue of the JCI, Yang et al. describe a proinflammatory phenotype resulting from deletion of the gene encoding the A2B adenosine receptor (A2BAR) in the mouse, suggesting that activation of the A2BAR can also have antiinflammatory effects (see the related article beginning on page 1913). Nevertheless, the role of the A2BAR remains enigmatic since its activation can either stimulate or inhibit the release of proinflammatory cytokines in different cells and tissues.
Joel Linden
Congenital hydrocephalus affects 0.1–0.3% of live births, with a high mortality rate (~50%) in the absence of surgical intervention. Although the insertion of shunts alleviates the symptoms of the majority of congenital cases, the molecular basis of hydrocephalus and the mechanisms of cerebrospinal fluid (CSF) circulation remain largely unknown. Two important players are the subcommissural organ/Reissner’s fiber (SCO/RF) complex and the ventricular ependymal (vel) cells that together facilitate the flow of the CSF through the narrow canals of the ventricular system. In this issue of the JCI, Lang et al. demonstrate that overexpression of the pituitary adenylate cyclase–activating polypeptide (PACAP) type I (PAC1) receptor gene results in abnormal development of the SCO and vel cells, leading to congenital hydrocephalus (see the related article beginning on page 1924). The ligand for the PAC1 receptor is the neuropeptide PACAP, which uncovers what the authors believe to be a novel role for this signaling cascade in the regulation of CSF circulation.
David J. Picketts
Liver X receptors (LXRs) broadly limit cholesterol accumulation by regulating expression of genes involved in cholesterol efflux and storage. In this issue of the JCI, Cummins et al. report that LXRα is involved in similar regulation in the adrenal cortex, but it also substantially modulates glucocorticoid synthesis (see the related article beginning on page 1902). LXRα deletion in mice increases the availability of adrenal cholesterol for steroid synthesis by decreasing the expression of cholesterol efflux transporters. Glucocorticoid synthesis requires intramitochondrial cholesterol transport mediated by the steroidogenic acute regulatory protein (StAR). Surprisingly, LXR deletion and stimulation by an agonist each increase glucocorticoid synthesis. This parallels increased expression of StAR and several other steroidogenic genes.
Colin R. Jefcoate
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