Charles B Wright

Iron Toxicity in the Retina Requires Alu RNA and the NLRP3 Inflammasome

Excess iron induces tissue damage and is implicated in age-related macular degeneration (AMD). Iron toxicity is widely attributed to hydroxyl radical formation through Fentons reaction. We report that excess iron, but not other Fenton catalytic metals, induces activation of the NLRP3 inflammasome, a pathway also implicated in AMD. Additionally, iron-induced degeneration of the retinal pigmented epithelium (RPE) is suppressed in mice lacking inflammasome components caspase-1/11 or Nlrp3 or by inhibition of caspase-1. Iron overload increases abundance of RNAs transcribed from short interspersed nuclear elements (SINEs): Alu RNAs and the rodent equivalent B1 and B2 RNAs, which are inflammasome agonists. Targeting Alu or B2 RNA prevents iron-induced inflammasome activation and RPE degeneration. Iron-induced SINE RNA accumulation is due to suppression of DICER1 via sequestration of the co-factor poly(C)-binding protein 2 (PCBP2). These findings reveal an unexpected mechanism of iron toxicity, with implications for AMD and neurodegenerative diseases associated with excess iron.

Human IgG1 antibodies suppress angiogenesis in a target-independent manner

Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world’s population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab’s Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

Intravenous immune globulin suppresses angiogenesis in mice and humans

Human intravenous immune globulin (IVIg), a purified IgG fraction composed of ~60% IgG1 and obtained from the pooled plasma of thousands of donors, is clinically used for a wide range of diseases. The biological actions of IVIg are incompletely understood and have been attributed both to the polyclonal antibodies therein and also to their IgG (IgG) Fc regions. Recently, we demonstrated that multiple therapeutic human IgG1 antibodies suppress angiogenesis in a target-independent manner via FcγRI, a high-affinity receptor for IgG1. Here we show that IVIg possesses similar anti-angiogenic activity and inhibited blood vessel growth in five different mouse models of prevalent human diseases, namely, neovascular age-related macular degeneration, corneal neovascularization, colorectal cancer, fibrosarcoma and peripheral arterial ischemic disease. Angioinhibition was mediated by the Fc region of IVIg, required FcγRI and had similar potency in transgenic mice expressing human FcγRs. Finally, IVIg therapy administered to humans for the treatment of inflammatory or autoimmune diseases reduced kidney and muscle blood vessel densities. These data place IVIg, an agent approved by the US Food and Drug Administration, as a novel angioinhibitory drug in doses that are currently administered in the clinical setting. In addition, they raise the possibility of an unintended effect of IVIg on blood vessels.

Dry Age-Related Macular Degeneration Pharmacology

Age-related macular degeneration (AMD), the most common form of irreversible blindness in the industrially developed world, can present years before a patient begins to lose vision. For most of these patients, AMD never progresses past its early stages to the advanced forms that are principally responsible for the vast majority of vision loss. Advanced AMD can manifest as either an advanced avascular form known as geographic atrophy (GA) marked by regional retinal pigment epithelium (RPE) cell death or as an advanced form known as neovascular AMD marked by the intrusion of fragile new blood vessels into the normally avascular retina. Physicians have several therapeutic interventions available to combat neovascular AMD, but GA has no approved effective therapies as of yet. In this chapter, we will discuss the current strategies for limiting dry AMD in patients. We will also discuss previous attempts at pharmacological intervention that were tested in a clinical setting and consider reasons why these putative therapeutics did not perform successfully in large-scale trials. Despite the number of unsuccessful past trials, new pharmacological interventions may succeed. These future therapies may aid millions of AMD patients worldwide.

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PhD trainees aspiring to become faculty need to know the credentials search committees value most in an applicant.

Closing Kynect and Restructuring Medicaid Threaten Kentucky's Health and Economy

Following passage of the Patient Protection and Affordable Care Act (ACA) in the United States, the Kentucky Health Benefit Exchange, Kynect, began operating in Kentucky in October 2013. Kentucky expanded Medicaid eligibility in January 2014. Together, Kynect and Medicaid expansion provided access to affordable health care coverage to hundreds of thousands of individuals in Kentucky. However, following the Kentucky gubernatorial election in 2015, the newly inaugurated governor moved to dismantle Kynect and restructure the Medicaid expansion, jeopardizing public health gains and the state economy. As the first state to announce both the closure and restructuring of a state health insurance marketplace and Medicaid expansion, Kentucky may serve as a test case for the rest of the nation for reversal of ACA-related health policies. This article describes Kynect and the Kentucky Medicaid expansion and examines the potential short-term and long-term impacts that may occur following changes in state health policy. Furthermore, this article will offer potential strategies to ameliorate the expected negative impacts of disruption of both Kynect and the Medicaid expansion, such as the creation of a new state insurance marketplace under a new governor, the implementation of a private option, and increasing the state minimum wage for workers.

Age-Related Macular Degeneration and Vision Impairment

Age-related macular degeneration (AMD) is a major contributing factor to non-reversible vision loss in the aging population in the developed world, but as of yet, it is still a poorly understood disease with few to no approved treatments, depending on the form of the disease. AMD has two primary forms: the non-exudative (dry) form and the exudative (wet) form. Many recent lines of evidence indicate that AMD may have a strong autoimmune component. The complement cascade, inflammasome, and angiogenic signaling pathways are of particular interest as targets for future therapeutic development. Herein we will discuss the potential roles that inflammation, angiogenesis, metal and lipid dysmetabolism, genetics and aging may play in the development and progression of AMD. Although there are no current effective therapies approved for the treatment of certain forms of AMD, the growing body of knowledge concerning the different facets of age-related processes associated with this disease offers a host of exciting new therapeutic approaches that will be the focus of future investigations.