Induction of interleukin-1β by activated microglia is a prerequisite for immunologically induced fatigue

Masataka Ifuku, Md. Shamim Hossain, Mami Noda, Toshihiko Katafuchi

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

We previously reported that an intraperitoneal (i.p.) injection of synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (poly-I:C), produced prolonged fatigue in rats, which might serve as a model for chronic fatigue syndrome. The poly-I:C-induced fatigue was associated with serotonin transporter (5-HTT) overexpression in the prefrontal cortex (PFC), a brain region that has been suggested to be critical for fatigue sensation. In the present study, we demonstrated that microglial activation in the PFC was important for poly-I:C-induced fatigue in rats, as pretreatment with minocycline, an inhibitor of microglial activation, prevented the decrease in running wheel activity. Poly-I:C injection increased the microglial interleukin (IL)-1β expression in the PFC. An intracerebroventricular (i.c.v.) injection of IL-1β neutralising antibody limited the poly-I:C-induced decrease in activity, whereas IL-1β (i.c.v.) reduced the activity in a dose-dependent manner. 5-HTT expression was enhanced by IL-1β in primary cultured astrocytes but not in microglia. Poly-I:C injection (i.p.) caused an increase in 5-HTT expression in astrocytes in the PFC of the rat, which was inhibited by pretreatment with minocycline (i.p.) and rat recombinant IL-1 receptor antagonist (i.c.v.). Poly-I:C injection (i.p.) led to a breakdown of the blood-brain barrier and enhanced Toll-like receptor 3 signaling in the brain. Furthermore, direct application of poly-I:C enhanced IL-1β expression in primary microglia. We therefore propose that poly-I:C-induced microglial activation, which may be at least partly caused by a direct action of poly-I:C, enhances IL-1β expression. Then, IL-1β induces 5-HTT expression in astrocytes, resulting in the immunologically induced fatigue.

Original languageEnglish
Pages (from-to)3253-3263
Number of pages11
JournalEuropean Journal of Neuroscience
Volume40
Issue number8
DOIs
Publication statusPublished - Oct 1 2014

Fingerprint

Microglia
Interleukin-1
Fatigue
Prefrontal Cortex
Poly I-C
Intraperitoneal Injections
Astrocytes
Minocycline
Toll-Like Receptor 3
Chronic Fatigue Syndrome
Serotonin Plasma Membrane Transport Proteins
Injections
Interleukin-1 Receptors
Double-Stranded RNA
Brain
polyriboinosinic-polyribocytidylic acid
Neutralizing Antibodies
Blood-Brain Barrier
Running

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Induction of interleukin-1β by activated microglia is a prerequisite for immunologically induced fatigue. / Ifuku, Masataka; Hossain, Md. Shamim; Noda, Mami; Katafuchi, Toshihiko.

In: European Journal of Neuroscience, Vol. 40, No. 8, 01.10.2014, p. 3253-3263.

Research output: Contribution to journalArticle

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abstract = "We previously reported that an intraperitoneal (i.p.) injection of synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (poly-I:C), produced prolonged fatigue in rats, which might serve as a model for chronic fatigue syndrome. The poly-I:C-induced fatigue was associated with serotonin transporter (5-HTT) overexpression in the prefrontal cortex (PFC), a brain region that has been suggested to be critical for fatigue sensation. In the present study, we demonstrated that microglial activation in the PFC was important for poly-I:C-induced fatigue in rats, as pretreatment with minocycline, an inhibitor of microglial activation, prevented the decrease in running wheel activity. Poly-I:C injection increased the microglial interleukin (IL)-1β expression in the PFC. An intracerebroventricular (i.c.v.) injection of IL-1β neutralising antibody limited the poly-I:C-induced decrease in activity, whereas IL-1β (i.c.v.) reduced the activity in a dose-dependent manner. 5-HTT expression was enhanced by IL-1β in primary cultured astrocytes but not in microglia. Poly-I:C injection (i.p.) caused an increase in 5-HTT expression in astrocytes in the PFC of the rat, which was inhibited by pretreatment with minocycline (i.p.) and rat recombinant IL-1 receptor antagonist (i.c.v.). Poly-I:C injection (i.p.) led to a breakdown of the blood-brain barrier and enhanced Toll-like receptor 3 signaling in the brain. Furthermore, direct application of poly-I:C enhanced IL-1β expression in primary microglia. We therefore propose that poly-I:C-induced microglial activation, which may be at least partly caused by a direct action of poly-I:C, enhances IL-1β expression. Then, IL-1β induces 5-HTT expression in astrocytes, resulting in the immunologically induced fatigue.",
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