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. 2019 May 17;16(1):102.
doi: 10.1186/s12974-019-1502-8.

Interleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjögren's syndrome

Kjetil Bårdsen  1   2 , Cato Brede  2   3 , Ingeborg Kvivik  1 , Jan Terje Kvaløy  1   4 , Kristin Jonsdottir  1 , Anne Bolette Tjensvoll  5 , Peter Ruoff  6 , Roald Omdal  7   8
Affiliations

Interleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjögren's syndrome

Kjetil Bårdsen et al. J Neuroinflammation. .

Abstract

Background: Fatigue is a common and sometimes debilitating phenomenon in primary Sjögren's syndrome (pSS) and other chronic inflammatory diseases. We aimed to investigate how IL-1 β-related molecules and the neuropeptide hypocretin-1 (Hcrt1), a regulator of wakefulness, influence fatigue.

Methods: Hcrt1 was measured by radioimmunoassay (RIA) in cerebrospinal fluid (CSF) from 49 patients with pSS. Interleukin-1 receptor antagonist (IL-1Ra), IL-1 receptor type 2 (IL-1RII), IL-6, and S100B protein were measured by enzyme-linked immunosorbent assay (ELISA). Fatigue was rated by the fatigue visual analog scale (fVAS).

Results: Simple univariate regression and multiple regression analyses with fatigue as a dependent variable revealed that depression, pain, and the biochemical variable IL-1Ra had a significant association with fatigue. In PCA, two significant components were revealed. The first component (PC1) was dominated by variables related to IL-1β activity (IL-1Ra, IL-1RII, and S100B). PC2 showed a negative association between IL-6 and Hcrt1. fVAS was then introduced as an additional variable. This new model demonstrated that fatigue had a higher association with the IL-1β-related PC1 than to PC2. Additionally, a third component (PC3) became significant between low Hcrt1 concentrations and fVAS scores.

Conclusions: The main findings of this study indicate a functional network in which several IL-1β-related molecules in CSF influence fatigue in addition to the classical clinical factors of depression and pain. The neuropeptide Hcrt1 seems to participate in fatigue generation, but likely not through the IL-1 pathway.

Keywords: Cytokines; Fatigue; Hypocretin; Innate immunity; Sjögren’s syndrome.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
a PCA of the biochemical variables only. b PCA of the biochemical variables and fatigue variable (fVAS). Bi-plot shows scores of the individuals and variable correlations for PC1 and PC2. Individual scores are illustrated by dots. Arrows illustrate the correlations of the variables to the components. Longer arrows mean higher correlation and arrows close to a component has a higher contribution in the generation of the component
Fig. 2
Fig. 2
Hypothetical model for fatigue. Danger signals activate astroglia to produce and release S100B that bind to TLR4 and RAGE receptors on microglia. Activated microglia produce IL-1β that bind specific receptors (IL-1R1/IL-1RAcPb) on neurons and induce sickness behavior. There are no specific receptors for IL-6 that can modulate neurons in the same manner as for IL-1β, but higher levels of IL-6 may through stimulation of TNFα synthesis reduce the amount of Hcrt-1 in neurons. Low levels of Hcrt-1 can lead to or modulate fatigue through unknown pathways
See this image and copyright information in PMC

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