FRACTALKINE/CX3CR1 CONTROLS MICROGLIAL ACTIVATION IN THE BRAIN AND RETINA DURING ACUTE ENDOTOXEMIA
Rolando Garza, Andrew Mendiola, Astrid Cardona.
The University of Texas at San Antonio, San Antonio, TX.
Microglia are the resident immune cells of the central nervous system (CNS) with key roles in immune surveillance, development, and injury repair. More specifically, in response to pathogens, inflammation, or neuronal damage, microglia can rapidly change their morphology and exert effector functions that can be either beneficial or detrimental. However, the mechanisms that control microglial protective versus toxic phenotype remains to be defined. Data from our laboratory has shown that the fractalkine receptor (CX3CR1), expressed exclusively on microglia in the CNS, controls microglial activation and neurotoxicity in animal models of systemic inflammation and autoimmune diseases. We hypothesized that fractalkine (CX3CL1) and CX3CR1 deficiency globally activates microglia in the brain and retina during acute endotoxemia. To study the role of CX3CR1 and its ligand, fractalkine (CX3CL1), on microglial activation, we generated Cx3cr1–/–(CX3CR1-KO) and Cx3cl1–/–(FKN-KO) mice. To extend these studies, we challenged CX3CR1-KO and FKN-KO mice with a low dose of lipopolysaccharide (20 µg/day) for 4 consecutive days to establish a low-level endotoxemia. Our data revealed that both CX3CR1-KO and FKN-KO lead to a robust activation and significant increase in microglial cells in the cortex, hippocampus, and superior colliculus during endotoxemia in contrast to WT mice. Interestingly, CX3CL1 and CX3CR1 deficiency correlated with an intense activation in retinal microglial that lead to phagocytic-like morphology and cell cluster near vessels following LPS treated. These data support our hypothesis that CX3CL1/CX3CR1 signaling controls microglial activation in the CNS and provides evidence that the retina is more sensitive to endotoxemia than the brain.