Recent Advances in IL-13Rα2-Directed Cancer Immunotherapy.

Interleukin-13 receptor subunit alpha-2 (IL-13Rα2, CD213A), a high-affinity membrane receptor of the anti-inflammatory Th2 cytokine IL-13, is overexpressed in a variety of solid tumors and is correlated with poor prognosis in glioblastoma, colorectal cancer, adrenocortical carcinoma, pancreatic cancer, and breast cancer. While initially hypothesized as a decoy receptor for IL-13-mediated signaling, recent evidence demonstrates IL-13 can signal through IL-13Rα2 in human cells. In addition, expression of IL-13Rα2 and IL-13Rα2-mediated signaling has been shown to promote tumor proliferation, cell survival, tumor progression, invasion, and metastasis. Given its differential expression in tumor versus normal tissue, IL-13Rα2 is an attractive immunotherapy target, as both a targetable receptor and an immunogenic antigen. Multiple promising strategies, including immunotoxins, cancer vaccines, and chimeric antigen receptor (CAR) T cells, have been developed to target IL-13Rα2. In this mini-review, we discuss recent developments surrounding IL-13Rα2-targeted therapies in pre-clinical and clinical study, including potential strategies to improve IL-13Rα2-directed cancer treatment efficacy.

Polychlorinated biphenyls induce oxidative stress and metabolic responses in astrocytes.

Exposure to environmental toxicants is prevalent, hazardous and linked to varied detrimental health outcomes and disease. Polychlorinated biphenyls (PCBs), a class of hazardous organic chlorines once widely used for industrial purposes, are associated with neurodegenerative disease and oxidative stress in both in vitro and in vivo models. Here, we investigated the impact of Aroclor 1254, a commercially available PCB mixture, on primary murine astrocytes to determine the response to this once ubiquitously used toxicant on the most numerous cells of the central nervous system (CNS). Astrocytes are a critical component of homeostasis throughout the CNS, including at the blood-brain barrier, where they serve as the primary defense against xenobiotics entering the CNS, and at the synapse, where they are closely coupled to neurons through several metabolic pathways. We hypothesized that PCBs cause astrocytic oxidative stress and related dysfunction including altered metabolism. We exposed primary murine cortical astrocytes to PCBs and report an increased expression of antioxidant genes (Prdx1, Gsta2, Gfap, Amigo2) in response to oxidative stress. Our data show increased ATP production and spare respiratory capacity in astrocytes exposed to 10 µM (∼ 3 ppm) PCBs. This dose also causes an increase in glucose uptake that is not seen at a higher dose (50 µM) suggesting that, at a lower dose, astrocytes are able to engage compensatory mechanisms to promote survival. Together, these data suggest that exposure to PCBs impact astrocytic metabolism, which is important to consider both in the context of human health and disease and in in vitro and in vivo disease models.

Environmental toxicants in the brain: A review of astrocytic metabolic dysfunction.

Exposure to environmental toxicants is linked to long-term adverse outcomes in the brain and involves the dysfunction of glial and neuronal cells. Astrocytes, the most numerous cell type, are increasingly implicated in the pathogenesis of many diseases of the central nervous system, including neurodegenerative diseases. Astrocytes are critical for proper brain function in part due to their robust antioxidant and unique metabolic capabilities. Additionally, astrocytes are positioned both at the blood-brain barrier, where they are the primary responders to xenobiotic penetrance of the CNS, and at synapses where they are in close contact with neurons and synaptic machinery. While exposure to several classes of environmental toxicants, including chlorinated and fluorinated compounds, and trace metals, have been implicated in neurodegenerative diseases, their impact on astrocytes represents an important and growing field of research. Here, we review existing literature focused on the impact of a range of synthetic compounds on astrocytic function. We focus specifically on perturbed metabolic processes in response to these compounds and consider how perturbation of these pathways impacts disease pathogenesis.

Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury.

BACKGROUND: Traumatic Brain Injury (TBI) is a major cause of disability and mortality, to which there is currently no comprehensive treatment. Blood Brain Barrier (BBB) dysfunction is well documented in human TBI patients, yet the molecular mechanisms that underlie this neurovascular unit (NVU) pathology remains unclear. The apolipoprotein-E (apoE) protein has been implicated in controlling BBB integrity in an isoform dependent manner, via suppression of Cyclophilin A (CypA)-Matrix metallopeptidase-9 (MMP-9) signaling cascades, however the contribution of this pathway in TBI-induced BBB permeability is not fully investigated. METHODS: We exposed C57Bl/6 mice to controlled cortical impact and assessed NVU and BBB permeability responses up to 21 days post-injury. We pharmacologically probed the role of the CypA-MMP-9 pathway in BBB permeability after TBI using Cyclosporin A (CsA, 20 mg/kg). Finally, as the apoE4 protein is known to be functionally deficient compared to the apoE3 protein, we used humanized APOE mice as a clinically relevant model to study the role of apoE on BBB injury and repair after TBI. RESULTS: In C57Bl/6 mice there was an inverse relationship between soluble apoE and BBB permeability, such that damaged BBB stabilizes as apoE levels increase in the days following TBI. TBI mice displayed acute pericyte loss, increased MMP-9 production and activity, and reduced tight-junction expression. Treatment with the CypA antagonist CsA in C57Bl/6 mice attenuates MMP-9 responses and enhances BBB repair after injury, demonstrating that MMP-9 plays an important role in the timing of spontaneous BBB repair after TBI. We also show that apoe mRNA is present in both astrocytes and pericytes after TBI. We report that APOE3 and APOE4 mice have similar acute BBB responses to TBI, but APOE3 mice display faster spontaneous BBB repair than APOE4 mice. Isolated microvessel analysis reveals delayed pericyte repopulation, augmented and sustained MMP-9 expression at the NVU, and impaired stabilization of Zonula Occludens-1, Occludin and Claudin-5 expression at tight junctions in APOE4 mice after TBI compared to APOE3 mice. CONCLUSIONS: These data confirm apoE as an important modulator of spontaneous BBB stabilization following TBI, and highlights the APOE4 allele as a risk factor for poor outcome after TBI.