ER Stress Protein CHOP Mediates Insulin Resistance by Modulating Adipose Tissue Macrophage Polarity

Obesity represents chronic inflammatory states promoted by pro-inflammatory M1-macrophage infiltration into white adipose tissue (WAT), thereby inducing insulin resistance. Herein, we demonstrate the importance of an ER stress protein, CHOP, in determining adipose tissue macrophage (ATM) polarity and systemic insulin sensitivity. A high-fat diet (HFD) enhances ER stress with CHOP upregulation in adipocytes. CHOP deficiency prevents HFD-induced insulin resistance and glucose intolerance with ATM M2 predomination and Th2 cytokine upregulation in WAT. Whereas ER stress suppresses Th2 cytokine expression in cultured adipocytes, CHOP knockdown inhibits this downregulation. In contrast, macrophage responsiveness to Th1/Th2 cytokines is unchanged regardless of whether CHOP is expressed. Furthermore, bone marrow transplantation experiments showed recipient CHOP to be the major determinant of ATM polarity. Thus, CHOP in adipocytes plays important roles in ATM M1 polarization by altering WAT micro-environmental conditions, including Th2 cytokine downregulation. This molecular mechanism may link adipose ER stress with systemic insulin resistance

Vitreous Hemorrhage Caused by Ruptured Retinal Macroaneurysm

Purpose: To report the clinical findings of 7 patients with a vitreous hemorrhage (VH) caused by a ruptured retinal macroaneurysm. Methods: Interventional case series. The medical records of 7 patients with a VH caused by a ruptured macroaneurysm and treated by either medication or vitrectomy were reviewed. The main outcome measures were the visual acuity, appearance of the fundus and optical coherence tomographic findings. Results: Two patients, aged 49 and 58 years, had retinal macroaneurysms at the optic disc. The retinal macroaneurysm in the other 5 eyes (mean age 79.0 years) was not at the optic disc. The VH was completely resolved in all 7 patients. The visual acuity improved in all eyes and remained stable for at least 6 months after the treatments (p = 0.0478). Conclusions: The improvement of the visual acuity in all eyes indicates that the prognosis of eyes with a VH caused by a ruptured retinal macroaneurysm is good

Choroidal Excavation in Eye with Normal Tension Glaucoma

Purpose: To report the case of an eye with normal tension glaucoma and a choroidal excavation. Methods: This is an observational case report. Results: A 59-year-old woman with normal tension glaucoma had a choroidal excavation in the left eye. Her best-corrected visual acuity and intraocular pressure were within normal limits and had been stable for 5 years. Fundus examination showed a small white lesion inferior to the macula and a nerve fiber layer defect at the inferior edge of the optic disc. Humphrey Field Analyzer (HFA) showed visual field defects corresponding to the nerve fiber layer defect with C30-2, and a central scotoma superior to the macula with C10-2. Optical coherence tomography (OCT) showed a 150-µm deep choroidal excavation. Disruptions of the IS/OS line were detected only in the area inferior to the choroidal excavation. During the 5 months of follow-up, her best-corrected visual acuity remained at 1.0 and the IOP ranged from 12 to 14 mm Hg in the left eye. The fundus and OCT images did not deteriorate and the choroidal excavation did not enlarge. Conclusions: The disruption of the inner/outer segment (IS/OS) line was detected only at the area surrounding the choroidal excavation. OCT examinations are useful in assessing the area of the residual IS/OS line, and HFA can be used to estimate the residual central visual field

Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage

Alterations in microbiota are known to affect kidney disease conditions. We have previously shown that germ-free conditions exacerbated adenine-induced kidney damage in mice; however, the mechanism by which this occurs has not been elucidated. To explore this mechanism, we examined the influence of germ-free conditions on purine metabolism and renal immune responses involved in the kidney damage. Germ-free mice showed higher expression levels of purine-metabolizing enzymes such as xanthine dehydrogenase, which converts adenine to a nephrotoxic byproduct 2,8-dihydroxyadenine (2,8-DHA). The germ-free mice also showed increased urinary excretion of allantoin, indicating enhanced purine metabolism. Metabolome analysis demonstrated marked differences in the purine metabolite levels in the feces of germ-free mice and mice with microbiota. Furthermore, unlike the germ-free condition, antibiotic treatment did not increase the expression of purine-metabolizing enzymes or exacerbate adenine-induced kidney damage. Considering renal immune responses, the germ-free mice displayed an absence of renal IL-17A expression. However, the adenine-induced kidney damage in wild-type mice was comparable to that in IL-17A-deficient mice, suggesting that IL-17A does not play a major role in the disease condition. Our results suggest that the enhanced host purine metabolism in the germ-free mice potentially promotes the conversion of the administered adenine into 2,8-DHA, resulting in exacerbated kidney damage. This further suggests a role of the microbiota in regulating host purine metabolism

Gene therapy model of X-linked severe combined immunodeficiency using a modified foamy virus vector.

X-linked severe combined immunodeficiency (SCID-X1) is an inherited genetic immunodeficiency associated with mutations in the common cytokine receptor γ chain (γc) gene, and characterized by a complete defect of T and natural killer (NK) cells. Gene therapy for SCID-X1 using conventional retroviral (RV) vectors carrying the γc gene results in the successful reconstitution of T cell immunity. However, the high incidence of vector-mediated T cell leukemia, caused by vector insertion near or within cancer-related genes has been a serious problem. In this study, we established a gene therapy model of mouse SCID-X1 using a modified foamy virus (FV) vector expressing human γc. Analysis of vector integration in a human T cell line demonstrated that the FV vector integration sites were significantly less likely to be located within or near transcriptional start sites than RV vector integration sites. To evaluate the therapeutic efficacy, bone marrow cells from γc-knockout (γc-KO) mice were infected with the FV vector and transplanted into γc-KO mice. Transplantation of the FV-treated cells resulted in the successful reconstitution of functionally active T and B cells. These data suggest that FV vectors can be effective and may be safer than conventional RV vectors for gene therapy for SCID-X1

ER Stress Protein CHOP Mediates Insulin Resistance by Modulating Adipose Tissue Macrophage Polarity

Obesity represents chronic inflammatory states promoted by pro-inflammatory M1-macrophage infiltration into white adipose tissue (WAT), thereby inducing insulin resistance. Herein, we demonstrate the importance of an ER stress protein, CHOP, in determining adipose tissue macrophage (ATM) polarity and systemic insulin sensitivity. A high-fat diet (HFD) enhances ER stress with CHOP upregulation in adipocytes. CHOP deficiency prevents HFD-induced insulin resistance and glucose intolerance with ATM M2 predomination and Th2 cytokine upregulation in WAT. Whereas ER stress suppresses Th2 cytokine expression in cultured adipocytes, CHOP knockdown inhibits this downregulation. In contrast, macrophage responsiveness to Th1/Th2 cytokines is unchanged regardless of whether CHOP is expressed. Furthermore, bone marrow transplantation experiments showed recipient CHOP to be the major determinant of ATM polarity. Thus, CHOP in adipocytes plays important roles in ATM M1 polarization by altering WAT micro-environmental conditions, including Th2 cytokine downregulation. This molecular mechanism may link adipose ER stress with systemic insulin resistance

Profile of provirus integration in transduced cells.

<p>(<b>A</b>) Position of FV and RV integration sites. The percentage of all integration sites within 15 kb of transcriptional start sites, within genes that contain putative microRNA genes, and within 30 kb of oncogenes is shown for FV vector- or RV vector-treated cells. *p<0.05, χ²-test. (<b>B</b>) A 100-kb window centered on TSS in the RefSeq database is shown. Relative frequencies of FV and RV vector integrations in each interval were calculated by dividing the percentage of integration b the indicated interval length.</p