title: MyD88-dependent pathways in leukocytes affect the retina in diabetes.
abstract: BACKGROUND
  Previous studies by us and other have provided evidence that leukocytes play a critical role in the development of diabetic retinopathy, suggesting a possible role of the innate immune system in development of the retinopathy. Since MyD88 is a convergence point for signaling pathways of the innate immune system (including Toll-Like Receptors (TLRs) and interleukin-1ß (IL-1ß)), the purpose of this study was to assess the role of MyD88 and its dependent pathways on abnormalities that develop in retina and white blood cells related to diabetic retinopathy.
  
  
  METHODS
  C57BL/6J mice were made diabetic with streptozotocin. Chimeric mice were generated in which MyD88-dependent pathways were deleted from bone marrow-derived only. Mice were sacrificed at 2 mos of diabetes for assessment of, leukostasis, albumin accumulation in neural retina, leukocyte-mediated killing of retinal endothelial cells, and cytokine/chemokine generation by retinas of diabetic mice in response to TLR agonists.
  
  
  RESULTS
  IL-6 and CXCL1 were generated in retinas from diabetic (but not nondiabetic mice) following incubation with Pam3CysK/TLR2, but incubation with other TLR ligands or IL-1ß did not induce cytokine production in retinas from nondiabetic or diabetic mice. Diabetes-induced abnormalities (leukostasis, ICAM-1 expression on the luminal surface of the vascular endothelium, retinal superoxide generation) were significantly inhibited by removing either MyD88 or the signaling pathways regulated by it (TLRs 2 and 4, and IL-1ß) from bone marrow-derived cells only. Leukocyte-mediated killing of endothelial cells tended to be decreased in the marrow-derived cells lacking TLR2/4, but the killing was significantly exacerbated if the marrow cells lacked MyD88 or the receptor for IL-1ß (IL-1ßr).
  
  
  CONCLUSIONS
  MyD88-dependent pathways play an important role in the development of diabetes-induced inflammation in the retina, and inhibition of MyD88 might be a novel target to inhibit early abnormalities of diabetic retinopathy and other complications of diabetes.
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Chieh
authors.initials: C
authors.lastname: Allen Lee
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Du
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Eric
authors.initials: E
authors.lastname: Pearlman
authors.forename: Nader
authors.initials: N
authors.lastname: Sheibani
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002199:Capillary Permeability / Q000276:immunology; D054360:Chemokine CXCL1 / Q000276:immunology / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000276:immunology* / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism; D018921:Leukostasis / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology* / Q000378:metabolism*; D012160:Retina / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1