title: Microglial Kv1.3 Channels and P2Y12 Receptors Differentially Regulate Cytokine and Chemokine Release from Brain Slices of Young Adult and Aged Mice.
abstract: Brain tissue damage following stroke or traumatic brain injury is accompanied by neuroinflammatory processes, while microglia play a central role in causing and regulating neuroinflammation via production of proinflammatory substances, including cytokines and chemokines. Here, we used brain slices, an established in situ brain injury model, from young adult and aged mice to investigate cytokine and chemokine production with particular focus on the role of microglia. Twenty four hours after slice preparation, higher concentrations of proinflammatory cytokines, i.e. TNF-α and IL-6, and chemokines, i.e. CCL2 and CXCL1, were released from brain slices of aged mice than from slices of young adult mice. However, maximal microglial stimulation with LPS for 24 h did not reveal age-dependent differences in the amounts of released cytokines and chemokines. Mechanisms underlying microglial cytokine and chemokine production appear to be similar in young adult and aged mice. Inhibition of microglial Kv1.3 channels with margatoxin reduced release of IL-6, but not release of CCL2 and CXCL1. In contrast, blockade of microglial P2Y12 receptors with PSB0739 inhibited release of CCL2 and CXCL1, whereas release of IL-6 remained unaffected. Cytokine and chemokine production was not reduced by inhibitors of Kir2.1 K+ channels or adenosine receptors. In summary, our data suggest that brain tissue damage-induced production of cytokines and chemokines is age-dependent, and differentially regulated by microglial Kv1.3 channels and P2Y12 receptors.
authors.affiliation: Institute for Infection and Immunity; St. George's, University of London; Cranmer Terrace; London SW17 0RE, United Kingdom.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Charolidi
authors.affiliation: Institute for Infection and Immunity; St. George's, University of London; Cranmer Terrace; London SW17 0RE, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Schilling
authors.affiliation: Institute for Infection and Immunity; St. George's, University of London; Cranmer Terrace; London SW17 0RE, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Eder
mesh_terms: D000375:Aging / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D051664:Kv1.3 Potassium Channel / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D008954:Models, Biological; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*
chemical_list: D018925:Chemokines; D016207:Cytokines; D051664:Kv1.3 Potassium Channel; D008070:Lipopolysaccharides; D058925:Receptors, Purinergic P2Y12