Adenosine A(2A) receptor mediates microglial process retraction. Nat Neurosci

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA.
Nature Neuroscience (Impact Factor: 16.1). 08/2009; 12(7):872-8. DOI: 10.1038/nn.2341
Source: PubMed


Cell motility drives many biological processes, including immune responses and embryonic development. In the brain, microglia are immune cells that survey and scavenge brain tissue using elaborate and motile cell processes. The motility of these processes is guided by the local release of chemoattractants. However, most microglial processes retract during prolonged brain injury or disease. This hallmark of brain inflammation remains unexplained. We identified a molecular pathway in mouse and human microglia that converted ATP-driven process extension into process retraction during inflammation. This chemotactic reversal was driven by upregulation of the A(2A) adenosine receptor coincident with P2Y(12) downregulation. Thus, A(2A) receptor stimulation by adenosine, a breakdown product of extracellular ATP, caused activated microglia to assume their characteristic amoeboid morphology during brain inflammation. Our results indicate that purine nucleotides provide an opportunity for context-dependent shifts in receptor signaling. Thus, we reveal an unexpected chemotactic switch that generates a hallmark feature of CNS inflammation.

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    • "With regards to the number of cells quantified for the microglial Process Length Analysis and End Point Voxel Analysis, we used all the cells in the field of view which ranged from $40 total cells in control tissues to up to $120 cells at POD7 after SNT. These data were used as measures of microglial morphology based on previous reports showing reduced microglia process branching complexity and process length during microglial activation (Fontainhas et al., 2011; Orr et al., 2009; Stence et al., 2001). The number of cell somas per frame was used to normalise all process endpoints and process lengths. "
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    • "Expressed at different levels (neurons, astrocytes, microglial cells), [17] [18] [19] [20] [21] it acts at various levels of regulation.[22] [23] [24] [25] Therefore, A 2A Rs are viewed as promising targets in various neurodegenerative diseases, mainly Parkinson's and Alzheimer's diseases.[26] [27] [28] Docking studies, based on the crystal structure of A 2A bound to the high affinity antagonist (ZM241385), [29] showed that Tic-guanidine restored hydrogen bonds that were missing for Tic-H leading us to expect a better affinity of these compounds.[30] "
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    European Journal of Medicinal Chemistry 10/2015; 106:15-25. DOI:10.1016/j.ejmech.2015.10.030 · 3.45 Impact Factor
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    • "Thus ATP is also considered as a danger signal (Inoue, 2008; Rodrigues et al., 2015; Sperl agh and Illes, 2007). With respect to microglia ATP acts as a multifactorial signal with various effects in microglia (Inoue, 2008; Orr et al., 2009). Neuronal loss due to excitotoxicity is a hallmark in epilepsy (Fujikawa, 2005), traumatic brain injury (Algattas and Huang, 2014), as well as in neurodegenerative diseases of the human CNS (Parsons and Raymond, 2014). "
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