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.