title: Interdependent and independent roles of type I interferons and IL-6 in innate immune, neuroinflammatory and sickness behaviour responses to systemic poly I:C.
abstract: Type I interferons (IFN-I) are expressed in the brain during many inflammatory and neurodegenerative conditions and have multiple effects on CNS function. IFN-I is readily induced in the brain by systemic administration of the viral mimetic, poly I:C (synthetic double-stranded RNA). We hypothesised that IFN-I contributes to systemically administered poly I:C-induced sickness behaviour, metabolic and neuroinflammatory changes. IFN-I receptor 1 deficient mice (IFNAR1(-/-)) displayed significantly attenuated poly I:C-induced hypothermia, hypoactivity and weight loss compared to WT C57BL/6 mice. This amelioration of sickness was associated with equivalent IL-1β and TNF-α responses but much reduced IL-6 responses in plasma, hypothalamus and hippocampus of IFNAR1(-/-) mice. IFN-β injection induced trivial IL-6 production and limited behavioural change and the poly I:C-induced IFN-β response did not preceed, and would not appear to mediate, IL-6 induction. Rather, IFNAR1(-/-) mice lack basal IFN-I activity, have lower STAT1 levels and show significantly lower levels of several inflammatory transcripts, including stat1. Basal IFN-I activity appears to play a facilitatory role in the full expression of the IL-6 response and activation of the tryptophan-kynurenine metabolism pathway. The deficient IL-6 response in IFNAR1(-/-) mice partially explains the observed incomplete sickness behaviour response. Reconstitution of circulating IL-6 revealed that the role of IFNAR in burrowing activity is mediated via IL-6, while IFN-I and IL-6 have additive effects on hypoactivity, but the role of IFN-I in anorexia is independent of IL-6. Hence, we have demonstrated both interdependent and independent roles for IFN-I and IL-6 in systemic inflammation-induced changes in brain function.
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland.
authors.forename: Carol
authors.initials: C
authors.lastname: Murray
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland.
authors.forename: Éadaoin W
authors.initials: ÉW
authors.lastname: Griffin
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland.
authors.forename: Elaine
authors.initials: E
authors.lastname: O'Loughlin
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland.
authors.forename: Aoife
authors.initials: A
authors.lastname: Lyons
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland.
authors.forename: Eoin
authors.initials: E
authors.lastname: Sherwin
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Ireland.
authors.forename: Suaad
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Ireland.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Stevenson
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Harkin
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland. Electronic address: colm.cunningham@tcd.ie.
authors.forename: Colm
authors.initials: C
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D055809:Illness Behavior / Q000187:drug effects* / Q000502:physiology; D007113:Immunity, Innate / Q000187:drug effects* / Q000502:physiology; D007249:Inflammation / Q000378:metabolism*; D007370:Interferon Type I / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011070:Poly I-C / Q000494:pharmacology*; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D053583:Interleukin-1beta; D015850:Interleukin-6; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D007737:Kynurenine; D014364:Tryptophan; D011070:Poly I-C
keywords: Behaviour; Burrowing; Cytokine; Depression; Hippocampus; Hypoactivity; IDO; IFN-α; IFN-β; IL-6; Interferon; Kynurenine; Neuroinflammation; STAT1; Sickness; Viral