title: CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes.
abstract: In this study, the role of CX3CR1 in the progression of diabetic retinopathy (DR) was investigated. The retinas of wild-type (WT), CX3CR1 null (CX3CR1gfp/gfp, KO), and heterozygous (CX3CR1+/gfp, Het) mice were compared in the presence and absence of streptozotocin (STZ)-induced diabetes. CX3CR1 deficiency in STZ-KO increased vascular pathology at 4 months of diabetes, as a significant increase in acellular capillaries was observed only in the STZ-KO group. CX3CR1 deficiency and diabetes had similar effects on retinal neurodegeneration measured by an increase in DNA fragmentation. Retinal vascular pathology in STZ-KO mice was associated with increased numbers of monocyte-derived macrophages in the retina. Furthermore, compared to STZ-WT, STZ-KO mice exhibited increased numbers of inflammatory monocytes in the bone marrow and impaired homing of monocytes to the spleen. The induction of retinal IL-10 expression by diabetes was significantly less in KO mice, and when bone marrow-derived macrophages from KO mice were maintained in high glucose, they expressed significantly less IL-10 and more TNF-α in response to LPS stimulation. These findings support that CX3CR1 deficiency accelerates the development of vascular pathology in DR through increased recruitment of proinflammatory myeloid cells that demonstrate reduced expression of anti-inflammatory IL-10.
  
  
  
  • CX3CR1 deletion in STZ-diabetic mice accelerated the onset of diabetic retinopathy (DR). • The early onset of DR was associated with increased retinal cell apoptosis. • The early onset of DR was associated with increased recruitment of bone marrow-derived macrophages to the retina. • Bone marrow-derived macrophages from CX3CR1 KO diabetic mice expressed more TNF-α and less IL-10. • The role of IL-10 in protection from progression of DR is highlighted.
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Eleni
authors.initials: E
authors.lastname: Beli
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Dominguez
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Thinschmidt
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Caballero
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Li Calzi
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Defang
authors.initials: D
authors.lastname: Luo
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, MI, USA.
authors.forename: Sumathi
authors.initials: S
authors.lastname: Shanmugam
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Tatiana E
authors.initials: TE
authors.lastname: Salazar
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Yaqian
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Boulton
authors.affiliation: Department of Physiology, Michigan State University, East Lancing, MI, USA.
authors.forename: Susanna
authors.initials: S
authors.lastname: Mohr
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, MI, USA.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Abcouwer
authors.affiliation: Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Saban
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Harrison
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA. mabgrant@iupui.edu.|Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA. mabgrant@iupui.edu.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
mesh_terms: D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D001854:Bone Marrow Cells / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1 / Q000172:deficiency* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology*; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D017353:Gene Deletion; D006442:Glycated Hemoglobin / Q000378:metabolism; D006706:Homeostasis; D007031:Hypothalamus / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D013311:Streptozocin
chemical_list: D000073883:CX3C Chemokine Receptor 1; D006442:Glycated Hemoglobin; D018836:Inflammation Mediators; D016753:Interleukin-10; D012333:RNA, Messenger; D013311:Streptozocin; C471885:Cx3cr1 protein, mouse
keywords: Apoptosis; CX3CR1; Diabetes; IL-10; Macrophages; Retinopathy