Regional neuroinflammation induced by peripheral infection contributes to fatigue-like symptoms: a [18F]DPA-714 positron emission tomography study in rats

Danxi Li; Di Hu; Yuta Ochi; Wakiko Arakaki; Aya Mawatari; Mika Shigeta; Yuping Wu; Emi Hayashinaka; Hiroyuki Neyama; Tsuyoshi Tahara; Yasuhiro Wada; Feng Li; Hisashi Doi; Yasuyoshi Watanabe; Yilong Cui

doi:10.3389/fimmu.2023.1261256

Regional neuroinflammation induced by peripheral infection contributes to fatigue-like symptoms: a [¹⁸F]DPA-714 positron emission tomography study in rats

Front Immunol. 2023 Nov 9:14:1261256. doi: 10.3389/fimmu.2023.1261256. eCollection 2023.

Authors

Danxi Li^#^{1

2

3}, Di Hu^#¹, Yuta Ochi^#¹, Wakiko Arakaki⁴, Aya Mawatari⁴, Mika Shigeta¹, Yuping Wu¹, Emi Hayashinaka⁵, Hiroyuki Neyama¹, Tsuyoshi Tahara¹, Yasuhiro Wada⁵, Feng Li², Hisashi Doi⁴, Yasuyoshi Watanabe⁵, Yilong Cui¹

Affiliations

¹ Laboratory for Biofunction Dynamics Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.
² Department of Chinese Medicine Diagnostics, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
³ Institute for Brain Disorders, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
⁴ Laboratory for Labeling Chemistry, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.
⁵ Laboratory for Pathophysiological and Health Science, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.

^# Contributed equally.

Abstract

Introduction: A series of symptoms, including fever, widespread pain, fatigue, and even ageusia, have frequently been reported in the context of various infections, such as COVID-19. Although the pathogenic mechanisms underlying an infection causing fever and pain have been well established, the mechanisms of fatigue induced by infection in specific brain regions remain unclear.

Methods: To elucidate whether and how the peripheral infection cause fatigue via regional neuroinflammation, we performed a brain-wide investigation of neuroinflammation in a peripheral pseudoinfection rat model using [¹⁸F]DPA-714 positron emission tomography (PET) imaging analysis, in which the polyriboinosinic: polyribocytidylic acid (poly I:C) was intraperitoneally injected.

Results: Transient fever lasting for several hours and subsequent suppression of spontaneous activity lasting a few days were induced by poly I:C treatment. Significant increase in plasma interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were observed at 2 and 4 h following poly I:C treatment. PET imaging analysis revealed that the brain uptake of [¹⁸F]DPA-714 was significantly increased in several brain regions one day after poly I:C treatment, such as the dorsal raphe (DR), parvicellular part of red nucleus (RPC), A5 and A7 noradrenergic nucleus, compared with the control group. The accumulation of [¹⁸F]DPA-714 in the DR, RPC and A5 was positively correlated with subsequent fatigue-like behavior, and that in the A7 tended to positively correlate with fever.

Discussion: These findings suggest that peripheral infection may trigger regional neuroinflammation, which may cause specific symptoms such as fatigue. A similar mechanism might be involved in COVID-19.

Keywords: PET; fatigue-like symptoms; peripheral infection; regional neuroinflammation; sickness behavior.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
COVID-19* / complications
Neuroinflammatory Diseases*
Pain
Poly I
Positron-Emission Tomography / methods
Rats

Substances

N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide
Poly I

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by JSPS KAKENHI [Grant Numbers JP17H02172, 20K21777]; and AMED [Grant Numbers JP18dk0310068, JP20ak0101059, JP20ak0101063].