title: Extracellular ATP differentially modulates Toll-like receptor 4-mediated cell survival and death of microglia.
abstract: The survival and death rates of inflammatory cells directly control their number and are substantially associated with the degree of inflammation. Microglia, key players in neuroinflammation, often cause excessive reactions implicated in neurological diseases. However, the mechanisms that determine microglial fate under pathological conditions remain to be elucidated. Here, we report that activation by lipopolysaccharide (LPS, a Toll-like receptor 4 ligand), an inflammation inducer, primarily promotes survival of microglia, but as its concentration is increased it induces cell death, resulting in decreased cell number. Moreover, extracellular ATP, which is released upon tissue damage, further enhanced the survival induced by a low LPS concentration and the death induced by a high LPS concentration. The survival-promoting effect of ATP was mimicked by non-hydrolyzable ATP analog, adenosine 5'-O-(3-thiotriphosphate), and also by the P2X(7) receptor agonist, 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate, and was suppressed by the P2X(7) antagonists, Brilliant Blue G and A 438079. On the contrary, the death of LPS-activated microglia was not affected by adenosine 5'-O-(3-thiotriphosphate), but enhanced by adenosine, ATP breakdown product. Thus, extracellular ATP modulates microglial survival and death in different ways involving P2X(7) receptor activation and ATP degradation to adenosine, respectively. Such Toll-like receptor 4/purinergic signaling may provide a fine regulatory system of neuroinflammation through modulating the microglial cell number.
authors.affiliation: Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Harada
authors.forename: Izumi
authors.initials: I
authors.lastname: Hide
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tanaka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakata
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D010975:Platelet Aggregation Inhibitors; D051197:Toll-Like Receptor 4; C022571:adenosine 5'-O-(3-thiotriphosphate); C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate