Systemic Inflammation Regulates Microglial Responses to Tissue Damage In Vivo

• Type of Material: Article
• Authors: Stefka Gyoneva, Emory University; Dimitrios Davalos, University of California San Francisco; Dipankar Biswas, University of Akron; Sharon Swanger, Emory University; Ethel Garnier-Amblard, Emory University; Francis Loth, University of Akron; Katerina Akassoglou, University of California San Francisco; Stephen Traynelis, Emory University
• Language: English
• Date: 2014-08-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Wiley Periodicals, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1002/glia.22686
• Title of Journal or Parent Work: Glia
• ISSN: 0894-1491
• Volume: 62
• Issue: 8
• Start Page: 1345
• End Page: 1360
• Grant/Funding Information: Funding was provided by the Pharmacological Sciences Institutional Training Grant T32GM008602 to S.G., Toxicology Institutional Training Grant T32ES12870 to S.G., NINDS NRSA F31NS076215 to S.G., internal pilot grant from the Udall Parkinson’s Disease Research Center at Emory University (NIH/NINDS P50-NS071669) to S.F.T, a Young Investigator Award from the Nancy Davis Foundation for Multiple Sclerosis to D.D., and NIH/NINDS grants NS052189 and NS066361 to K.A.
• Keywords: ADENOSINE; SEPSIS; CELLS; motility; ACTIVATION; A(2A) receptors; neuroinflammation; imaging; RODENT MODELS; Neurosciences & Neurology; NEUROINFLAMMATION; ATP; microglia; BRAIN; Life Sciences & Biomedicine; A(2A) RECEPTOR ANTAGONISTS; Science & Technology; PHAGOCYTOSIS; Neurosciences
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

Microglia, the resident immune cells of the central nervous system, exist in either a "resting" state associated with physiological tissue surveillance or an "activated" state in neuroinflammation. We recently showed that ATP is the primary chemoattractor to tissue damage in vivo and elicits opposite effects on the motility of activated microglia in vitro through activation of adenosine A2A receptors. However, whether systemic inflammation affects microglial responses to tissue damage in vivo remains largely unknown. Using in vivo two-photon imaging of mice, we show that injection of lipopolysaccharide (LPS) at levels that can produce both clear neuroinflammation and some features of sepsis significantly reduced the rate of microglial response to laser-induced ablation injury in vivo. Under proinflammatory conditions, microglial processes initially retracted from the ablation site, but subsequently moved toward and engulfed the damaged area. Analyzing the process dynamics in 3D cultures of primary microglia indicated that only A2A, but not A1 or A3 receptors, mediate process retraction in LPS-activated microglia. The A2A receptor antagonists caffeine and preladenant reduced adenosine-mediated process retraction in activated microglia in vitro. Finally, administration of preladenant before induction of laser ablation in vivo accelerated the microglial response to injury following systemic inflammation. The regulation of rapid microglial responses to sites of injury by A2A receptors could have implications for their ability to respond to the neuronal death occurring under conditions of neuroinflammation in neurodegenerative disorders. GLIA 2014;62:1345-1360 Main Points: Peripheral LPS treatment results in microglial activation and morphological transformation, altered baseline process motility and delayed response to laser-induced tissue damage as assessed with two-photon microscopy. Administration of the adenosine A2A receptor antagonist preladenant improves the ability of microglia to respond to tissue damage. The altered microglial motility under baseline and injury conditions could affect the ability of microglia to detect and clear cellular debris from cell death as it occurs during degenerative diseases.