title: Requirement for interleukin-1 to drive brain inflammation reveals tissue-specific mechanisms of innate immunity.
abstract: The immune system is implicated in a wide range of disorders affecting the brain and is, therefore, an attractive target for therapy. Interleukin-1 (IL-1) is a potent regulator of the innate immune system important for host defense but is also associated with injury and disease in the brain. Here, we show that IL-1 is a key mediator driving an innate immune response to inflammatory challenge in the mouse brain but is dispensable in extracerebral tissues including the lung and peritoneum. We also demonstrate that IL-1α is an important ligand contributing to the CNS dependence on IL-1 and that IL-1 derived from the CNS compartment (most likely microglia) is the major source driving this effect. These data reveal previously unknown tissue-specific requirements for IL-1 in driving innate immunity and suggest that IL-1-mediated inflammation in the brain could be selectively targeted without compromising systemic innate immune responses that are important for resistance to infection. This property could be exploited to mitigate injury- and disease-associated inflammation in the brain without increasing susceptibility to systemic infection, an important complication in several neurological disorders.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Giles
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Greenhalgh
authors.forename: Claire L
authors.initials: CL
authors.lastname: Davies
authors.forename: Adam
authors.initials: A
authors.lastname: Denes
authors.forename: Tovah
authors.initials: T
authors.lastname: Shaw
authors.forename: Graham
authors.initials: G
authors.lastname: Coutts
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Rothwell
authors.forename: Barry W
authors.initials: BW
authors.lastname: McColl
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Allan
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology* / Q000473:pathology; D004660:Encephalitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D007276:Injections, Intraventricular; D053582:Interleukin-1alpha / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D053583:Interleukin-1beta / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D008070:Lipopolysaccharides; D008168:Lung / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D009928:Organ Specificity; D010537:Peritoneum / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008070:Lipopolysaccharides
keywords: innate immunity; interleukin-1 (IL-1); neuroinflammation; neutrophil