title: Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury.
abstract: Excessive inflammation has been implicated in the progressive neurodegeneration that occurs in multiple neurological diseases, including cerebral ischemia, and elevated levels of the proinflammatory cytokine interleukin-1 (IL-1) have been shown to exacerbate brain damage, whereas diminishing IL-1 levels limits the extent of injury. However, to date there is no consensus regarding which receptor(s) mediates the detrimental effects of IL-1. Because we have previously demonstrated that signaling through the IL-1 type 1 receptor (IL-1R1) is necessary for microglial activation and because results from other studies have implicated microglia as effectors of neurodegeneration, we hypothesized that inactivating the IL-1R1 would decrease the extent of damage caused by a hypoxic-ischemic (H/I) insult. It is shown that a mild insult initiates progressive neurodegeneration that leads to cystic infarcts, which can be prevented by inactivating the IL-1R1. The IL-1R1 null mice also show preserved sensorimotor function at 1 month's recovery. The mild insult induces multiple proinflammatory cytokines and activates microglia, and these responses are dramatically curtailed in mice lacking the IL-1R1. Importantly, the neuroinflammation precedes the progressive enlargement of the infarct, suggesting that the inflammation is causal rather than a consequence of the brain damage. These findings show that abrogating the inflammation consequent to a mild H/I insult will prevent brain damage and preserve neurological function. Additionally, these data incriminate the IL-1R1 as a master proinflammatory cytokine receptor.
authors.affiliation: Departments of Neural and Behavioral Sciences, Radiology and Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Basu
authors.forename: Jelena
authors.initials: J
authors.lastname: Lazovic
authors.forename: J Kyle
authors.initials: JK
authors.lastname: Krady
authors.forename: David T
authors.initials: DT
authors.lastname: Mauger
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Rothstein
authors.forename: Michael B
authors.initials: MB
authors.lastname: Smith
authors.forename: Steven W
authors.initials: SW
authors.lastname: Levison
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D020271:Heredodegenerative Disorders, Nervous System / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000235:genetics / Q000502:physiology*
chemical_list: D017472:Receptors, Interleukin-1