title: Fractalkine Signaling Attenuates Perivascular Clustering of Microglia and Fibrinogen Leakage during Systemic Inflammation in Mouse Models of Diabetic Retinopathy.
abstract: Fractalkine (FKN) is a chemokine expressed constitutively by healthy neurons and signals to microglia upon interaction with the FKN receptor, CX3CR1. Signaling between FKN and CX3CR1 transduces inhibitory signals that ameliorate microglial activation and proinflammatory cytokine release in neuroinflammatory conditions. The aim of this study is to determine the mechanisms associated with microglial activation and vascular leakage during diabetic retinopathy (DR) and under conditions of low-level endotoxemia, common in diabetic patients. Utilizing the Ins2Akitastrain (Akita), a mouse model of type 1 diabetes, our results show that leakage of the blood-protein fibrin(ogen) into the retina occurs as a result of chronic (4 months) but not acute (1.5 months) hyperglycemia. Conversely, inducing endotoxin-mediated systemic inflammation during acute diabetes resulted in fibrinogen deposition in the retina, a phenotype that was exacerbated in mice lacking CX3CR1 signaling. Systemic inflammation inCx3cr1-/-mice led to robust perivascular clustering of proliferating microglia in areas of fibrinogen extravasation, and induced IL-1β expression in microglia and astrocytes. Lastly, we determined a protective effect of modulating FKN/CX3CR1 signaling in the diabetic retina. We show that intravitreal (iv) administration of recombinant FKN into diabetic FKN-KO mice, reduced fibrinogen deposition and perivascular clustering of microglia in the retina during systemic inflammation. These data suggest that dysregulated microglial activation via loss of FKN/CX3CR1 signaling disrupts the vascular integrity in retina during systemic inflammation.
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio San Antonio, TX, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Mendiola
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio San Antonio, TX, USA.
authors.forename: Rolando
authors.initials: R
authors.lastname: Garza
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio San Antonio, TX, USA.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardona
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio San Antonio, TX, USA.
authors.forename: Shannon A
authors.initials: SA
authors.lastname: Mythen
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai New York, NY, USA.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San FranciscoSan Francisco, CA, USA; Department of Neurology, University of California, San FranciscoSan Francisco, CA, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Akassoglou
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio San Antonio, TX, USA.
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Cardona
keywords: CX3CR1; diabetic retinopathy; fibrinogen; fractalkine; microglia; retina