title: The acute-phase protein PTX3 is an essential mediator of glial scar formation and resolution of brain edema after ischemic injury.
abstract: Acute-phase proteins (APPs) are key effectors of the immune response and are routinely used as biomarkers in cerebrovascular diseases, but their role during brain inflammation remains largely unknown. Elevated circulating levels of the acute-phase protein pentraxin-3 (PTX3) are associated with worse outcome in stroke patients. Here we show that PTX3 is expressed in neurons and glia in response to cerebral ischemia, and that the proinflammatory cytokine interleukin-1 (IL-1) is a key driver of PTX3 expression in the brain after experimental stroke. Gene deletion of PTX3 had no significant effects on acute ischemic brain injury. In contrast, the absence of PTX3 strongly compromised blood-brain barrier integrity and resolution of brain edema during recovery after ischemic injury. Compromised resolution of brain edema in PTX3-deficient mice was associated with impaired glial scar formation and alterations in scar-associated extracellular matrix production. Our results suggest that PTX3 expression induced by proinflammatory signals after ischemic brain injury is a critical effector of edema resolution and glial scar formation. This highlights the potential role for inflammatory molecules in brain recovery after injury and identifies APPs, in particular PTX3, as important targets in ischemic stroke and possibly other brain inflammatory disorders.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Rodriguez-Grande
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Matimba
authors.initials: M
authors.lastname: Swana
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Loan
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Pavlos
authors.initials: P
authors.lastname: Englezou
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Samaneh
authors.initials: S
authors.lastname: Maysami
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Allan
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Rothwell
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, MI, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garlanda
authors.affiliation: 1] Faculty of Life Sciences, University of Manchester, Manchester, UK [2] Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary.
authors.forename: Adam
authors.initials: A
authors.lastname: Denes
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pinteaux
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002921:Cicatrix / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D009419:Nerve Tissue Proteins; D000099153:Pentraxins