IL-33 and its decoy sST2 in patients with Alzheimer’s disease and mild cognitive impairment

Abstract

Background: Interleukin-33 is a cytokine endowed with pro-and anti-inflammatory properties that plays a still poorly defined role in the pathogenesis of a number of central nervous system (CNS) conditions including Alzheimer's disease (AD). We analyzed this cytokine and its decoy receptor sST2 in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Method: IL-33 and sST2 were analyzed in serum and CSF of AD and MCI patients, comparing the results to those obtained in age-matched healthy controls (HC). Because of the ambiguous role of IL-33 in inflammation, the concentration of both inflammatory (IL-1β and IL-6) and anti-inflammatory (IL-10) cytokines was analyzed as well in serum and cerebrospinal fluid (CSF) of the same individuals. Finally, the effect of IL-33 on in vitro Aβ 42-stimulated monocytes of AD, MCI, and HC individuals was examined. Results: As compared to HC, (1) IL-33 was significantly decreased in serum and CSF of AD and MCI, (2) sST2 was increased in serum of AD and MCI but was undetectable in CSF, (3) serum and CSF IL-1β concentration was significantly increased and that of IL-10 was reduced in AD and MCI, whereas no differences were observed in IL-6. In vitro addition of IL-33 to LPS+Aβ 42-stimulated monocytes downregulated IL-1β generation in MCI and HC, but not in AD, and stimulated IL-10 production in HC alone. IL-33 addition also resulted in a significant reduction of NF-kB nuclear translocation in LPS+Aβ 42-stimulated monocytes of HC alone. Conclusions: These data support the hypothesis that IL-33 plays a complex anti-inflammatory role that is lost in AD-and MCI-associated neuroinflammation; results herein also suggest a possible use of IL-33 as a novel therapeutic approach in AD and MCI.

Therapeutic Potential of a Combination of Electroacupuncture and Human iPSC-Derived Small Extracellular Vesicles for Ischemic Stroke

“…Interleukin (IL)-33, from the IL-1 cytokines family, is widely expressed in brains and spinal cords of human and rodent [ 16 , 17 ]. Emerging evidence increasingly implicates a pleiotropic role of IL-33 on regulating T lymphocyte immune responses [ 18 , 19 , 20 ]. IL-33 functions both as a transcription factor upon an interaction with chromosomes and as a traditional cytokine released from necrotic cells, acting as alarmin to alert the body to tissue injury [ 17 , 21 ].…”

Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus

“…In the most recent study of this type, in vitro application of IL-33 to lipopolysaccharide-primed, Aβ 42 -stimulated monocytes reduced IL-1β production in monocytes from healthy elderly adults and adults with MCI but not in cells from people with AD dementia; moreover, it stimulated IL-10 production in monocytes from healthy older adults only. Collectively, these findings suggest that anti-inflammatory functional pathways may be altered in the MCI and dementia stages 48 . Other studies have also linked hyperreactive peripheral innate immune cells with clinical outcomes in patients with AD.…”

“…Although most human studies of immune dysfunction and AD stages have focused on plasma cytokine levels, phenotypic and functional assays of monocytes have also indicated a role for inflammatory dysregulation in AD dementia 47 , 48 . In the most recent study of this type, in vitro application of IL-33 to lipopolysaccharide-primed, Aβ 42 -stimulated monocytes reduced IL-1β production in monocytes from healthy elderly adults and adults with MCI but not in cells from people with AD dementia; moreover, it stimulated IL-10 production in monocytes from healthy older adults only.…”

Therapeutic Opportunities of Interleukin-33 in the Central Nervous System

“…Although IL-33-positive cells (astrocytes and microglia) are significantly increased in Alzheimer's disease (AD) brains compared to non-AD brains (87), IL-33 mRNA expression in the brain (88) and circulating IL-33 levels (89) are lower in AD patients than in healthy controls. The decreased circulating IL-33 levels in AD might be attributed to the increased decoy receptor sST2 in the blood of AD patients (89). Three single nucleotide polymorphisms (SNPs), rs1157505, rs11792633 and rs7044343, within IL-33 have been reported to be associated with AD risk in a large prospective study in a Caucasian population.…”