title: CD40 in Retinal Müller Cells Induces P2X7-Dependent Cytokine Expression in Macrophages/Microglia in Diabetic Mice and Development of Early Experimental Diabetic Retinopathy.
abstract: Müller cells and macrophages/microglia are likely important for the development of diabetic retinopathy; however, the interplay between these cells in this disease is not well understood. An inflammatory process is linked to the onset of experimental diabetic retinopathy. CD40 deficiency impairs this process and prevents diabetic retinopathy. Using mice with CD40 expression restricted to Müller cells, we identified a mechanism by which Müller cells trigger proinflammatory cytokine expression in myeloid cells. During diabetes, mice with CD40 expressed in Müller cells upregulated retinal tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), intracellular adhesion molecule 1 (ICAM-1), and nitric oxide synthase (NOS2), developed leukostasis and capillary degeneration. However, CD40 did not cause TNF-α or IL-1β secretion in Müller cells. TNF-α was not detected in Müller cells from diabetic mice with CD40+Müller cells. Rather, TNF-α was upregulated in macrophages/microglia. CD40 ligation in Müller cells triggered phospholipase C-dependent ATP release that caused P2X7-dependent production of TNF-α and IL-1β by macrophages. P2X7-/-mice and mice treated with a P2X7inhibitor were protected from diabetes-induced TNF-α, IL-1β, ICAM-1, and NOS2 upregulation. Our studies indicate that CD40 in Müller cells is sufficient to upregulate retinal inflammatory markers and appears to promote experimental diabetic retinopathy and that Müller cells orchestrate inflammatory responses in myeloid cells through a CD40-ATP-P2X7pathway.
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH.
authors.forename: Jose-Andres C
authors.initials: JC
authors.lastname: Portillo
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH.
authors.forename: Yalitza
authors.initials: Y
authors.lastname: Lopez Corcino
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Miao
authors.affiliation: Division of Molecular Endocrinology, Department of Medicine, Case Western Reserve University, Cleveland, OH.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Ophthalmology, University of Wisconsin-Madison, Madison, WI.
authors.forename: Nader
authors.initials: N
authors.lastname: Sheibani
authors.affiliation: Division of Molecular Endocrinology, Department of Medicine, Case Western Reserve University, Cleveland, OH.|Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH.|Louis Stokes Cleveland Veterans Administration Medical Center, Research Service 151, Cleveland, OH.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH.
authors.forename: George R
authors.initials: GR
authors.lastname: Dubyak
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH carlos.subauste@case.edu.|Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH.|Department of Pathology, Case Western Reserve University, Cleveland, OH.
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Subauste
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology*; D002196:Capillaries; D016207:Cytokines / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000276:immunology*; D003930:Diabetic Retinopathy / Q000209:etiology / Q000276:immunology*; D063928:Ependymoglial Cells / Q000276:immunology*; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D018921:Leukostasis / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D010738:Type C Phospholipases / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; C587672:IL1B protein, mouse; C090509:Icam1 protein, mouse; D053583:Interleukin-1beta; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D010738:Type C Phospholipases