title: Disruption of Fractalkine Signaling Leads to Microglial Activation and Neuronal Damage in the Diabetic Retina.
abstract: Fractalkine (CX3CL1 or FKN) is a membrane-bound chemokine expressed on neuronal membranes and is proteolytically cleaved to shed a soluble chemoattractant domain. FKN signals via its unique receptor CX3CR1 expressed on microglia and other peripheral leukocytes. The aim of this study is to determine the role of CX3CR1 in inflammatory-mediated damage to retinal neurons using a model of diabetic retinopathy. For this, we compared neuronal, microglial, and astroglial densities and inflammatory response in nondiabetic and diabetic (Ins2(Akita)) CX3CR1-wild-type and CX3CR1-deficient mice at 10 and 20 weeks of age. Our results show that Ins2(Akita) CX3CR1-knockout mice exhibited (a) decreased neuronal cell counts in the retinal ganglion cell layer, (b) increased microglial cell numbers, and (c) decreased astrocyte responses comparable with Ins2(Akita) CX3CR1-Wild-type mice at 20 weeks of age. Analyses of the inflammatory response using PCR arrays showed several inflammatory genes differentially regulated in diabetic tissues. From those, the response in Ins2(Akita) CX3CR1-deficient mice at 10 weeks of age revealed a significant upregulation of IL-1β at the transcript level that was confirmed by enzyme-linked immunosorbent assay in soluble retinal extracts. Overall, IL-1β, VEGF, and nitrite levels as a read out of nitric oxide production were abundant in Ins2(Akita) CX3CR1-deficient retina. Notably, double immunofluorescence staining shows that astrocytes act as a source of IL-1β in the Ins2(Akita) retina, and CX3CR1-deficient microglia potentiate the inflammatory response via IL-1β release. Collectively, these data demonstrate that dysregulated microglial responses in absence of CX3CR1 contribute to inflammatory-mediated damage of neurons in the diabetic retina.
authors.affiliation: Department of Biology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, TX, USA.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardona
authors.affiliation: Department of Biology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, TX, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Mendiola
authors.affiliation: Department of Biology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, TX, USA.
authors.forename: Ya-Chin
authors.initials: YC
authors.lastname: Yang
authors.affiliation: Department of Biology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, TX, USA.
authors.forename: Sarina L
authors.initials: SL
authors.lastname: Adkins
authors.affiliation: Department of Biology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, TX, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Torres
authors.affiliation: Department of Biology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, TX, USA astrid.cardona@utsa.edu.
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Cardona
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology*; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology / Q000502:physiology*; D015213:Neuroimmunomodulation / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D012160:Retina / Q000473:pathology / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D009573:Nitrites; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D009569:Nitric Oxide
keywords: CX3CR1; fractalkine; inflammation; microglia; neurodegeneration; retinal ganglion cell