Brain interleukin-1β and the intrinsic receptor antagonist control peripheral Toll-like receptor 3-mediated suppression of spontaneous activity in rats

PLoS One. 2014 Mar 12;9(3):e90950. doi: 10.1371/journal.pone.0090950. eCollection 2014.

Abstract

During acute viral infections such as influenza, humans often experience not only transient fever, but also prolonged fatigue or depressive feelings with a decrease in social activity for days or weeks. These feelings are thought to be due to neuroinflammation in the brain. Recent studies have suggested that chronic neuroinflammation is a precipitating event of various neurological disorders, but the mechanism determining the duration of neuroinflammation has not been elucidated. In this study, neuroinflammation was induced by intraperitoneal injection of polyriboinosinic:polyribocytidylic acid (poly I:C), a Toll-like receptor-3 agonist that mimics viral infection in male Sprague-Dawley rats, and then investigated how the neuroinflammation shift from acute to the chronic state. The rats showed transient fever and prolonged suppression of spontaneous activity for several days following poly I:C injection. NS-398, a cyclooxygenase-2 inhibitor, completely prevented fever, but did not improve spontaneous activity, indicating that suppression of spontaneous activity was not induced by the arachidonate cascade that generated the fever. The animals overexpressed interleukin (IL)-1β and IL-1 receptor antagonist (IL-1ra) in the brain including the cerebral cortex. Blocking the IL-1 receptor in the brain by intracerebroventricular (i.c.v.) infusion of recombinant IL-1ra completely blocked the poly I:C-induced suppression of spontaneous activity and attenuated amplification of brain interferon (IFN)-α expression, which has been reported to produce fatigue-like behavior by suppressing the serotonergic system. Furthermore, i.c.v. infusion of neutralizing antibody for IL-1ra prolonged recovery from suppression of spontaneous activity. Our findings indicated that IL-1β is the key trigger of neuroinflammation and that IL-1ra prevents the neuroinflammation entering the chronic state.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal* / drug effects
  • Brain / drug effects
  • Brain / metabolism*
  • Interferon-alpha / genetics
  • Interleukin 1 Receptor Antagonist Protein / metabolism*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism*
  • Male
  • Nitrobenzenes / pharmacology
  • Poly I-C / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sulfonamides / pharmacology
  • Toll-Like Receptor 3 / metabolism*

Substances

  • Interferon-alpha
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • Nitrobenzenes
  • RNA, Messenger
  • Sulfonamides
  • Toll-Like Receptor 3
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Poly I-C

Grants and funding

This study was supported in part by the Core Research for Evolution Science and Technology (CREST) of Japan Science and Technology (JST), Grant-in-Aid for Scientific Research C (MEXT KAKENHI Grant Number 25460399 to Y.K), and Grant-in-Aid for Young Scientists B (MEXT KAKENHI Grant Number 25750169 to M.Y.), Grant-in-Aid for Scientific Research on Innovative Areas (MEXT KAKENHI Grant Number 25108515 to Y.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.