Circulating levels of IL-1 family cytokines and receptors in Alzheimer's disease: new markers of disease progression?

Affiliations

¹ Laboratory of Innate Immunity and Inflammation, Institute of Protein Biochemistry, National Research Council, Via Pietro Castellino 111, 80131, Naples, Italy.
² Clinical Immunology Unit, Department Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126, Pisa, Italy.
³ NeurOmics Laboratory, Institute of Protein Biochemistry, National Research Council, Via Pietro Castellino 111, 80131, Naples, Italy.
⁴ Centre for Research and Training in Medicine for Aging, Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Località Tappino, 86100, Campobasso, Italy.
⁵ Laboratory of Innate Immunity and Inflammation, Institute of Protein Biochemistry, National Research Council, Via Pietro Castellino 111, 80131, Naples, Italy. diana.boraschi@ibp.cnr.it.
⁶ NeurOmics Laboratory, Institute of Protein Biochemistry, National Research Council, Via Pietro Castellino 111, 80131, Naples, Italy. emilia.vitale@cnr.it.

PMID: 30541566
PMCID: PMC6292179
DOI: 10.1186/s12974-018-1376-1

Circulating levels of IL-1 family cytokines and receptors in Alzheimer's disease: new markers of disease progression?

Paola Italiani et al. J Neuroinflammation. 2018.

. 2018 Dec 12;15(1):342.

doi: 10.1186/s12974-018-1376-1.

Affiliations

¹ Laboratory of Innate Immunity and Inflammation, Institute of Protein Biochemistry, National Research Council, Via Pietro Castellino 111, 80131, Naples, Italy.
² Clinical Immunology Unit, Department Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126, Pisa, Italy.
³ NeurOmics Laboratory, Institute of Protein Biochemistry, National Research Council, Via Pietro Castellino 111, 80131, Naples, Italy.
⁴ Centre for Research and Training in Medicine for Aging, Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Località Tappino, 86100, Campobasso, Italy.
⁵ Laboratory of Innate Immunity and Inflammation, Institute of Protein Biochemistry, National Research Council, Via Pietro Castellino 111, 80131, Naples, Italy. diana.boraschi@ibp.cnr.it.
⁶ NeurOmics Laboratory, Institute of Protein Biochemistry, National Research Council, Via Pietro Castellino 111, 80131, Naples, Italy. emilia.vitale@cnr.it.

PMID: 30541566
PMCID: PMC6292179
DOI: 10.1186/s12974-018-1376-1

Abstract

Background: Although the mechanisms underlying AD neurodegeneration are not fully understood, it is now recognised that inflammation could play a crucial role in the initiation and progression of AD neurodegeneration. A neuro-inflammatory network, based on the anomalous activation of microglial cells, includes the production of a number of inflammatory cytokines both locally and systemically. These may serve as diagnostic markers or therapeutic targets for AD neurodegeneration.

Methods: We have measured the levels of the inflammation-related cytokines and receptors of the IL-1 family in serum of subjects with AD, compared to mild cognitive impairment (MCI), subjective memory complaints (SMC), and normal healthy subjects (NHS). Using a custom-made multiplex ELISA array, we examined ten factors of the IL-1 family, the inflammation-related cytokines IL-1α, IL-1β, IL-18, and IL-33, the natural inhibitors IL-1Ra and IL-18BP, and the soluble receptors sIL-1R1, sIL-1R2, sIL-1R3, and sIL-1R4.

Results: The inflammatory cytokines IL-1α and IL-1β, their antagonist IL-1Ra, and their soluble receptor sIL-1R1 were increased in AD. The decoy IL-1 receptor sIL-1R2 was only increased in MCI. IL-33 and its soluble receptor sIL-1R4 were also significantly higher in AD. The soluble form of the accessory receptor for both IL-1 and IL-33 receptor complexes, sIL-1R3, was increased in SMC and even more in AD. Total IL-18 levels were unchanged, whereas the inhibitor IL-18BP was significantly reduced in MCI and SMC, and highly increased in AD. The levels of free IL-18 were significantly higher in MCI.

Conclusions: AD is characterised by a significant alteration in the circulating levels of the cytokines and receptors of the IL-1 family. The elevation of sIL-1R4 in AD is in agreement with findings in other diseases and can be considered a marker of ongoing inflammation. Increased levels of IL-1Ra, sIL-1R1, sIL-1R4, and IL-18BP distinguished AD from MCI and SMC, and from other inflammatory diseases. Importantly, sIL-1R1, sIL-1R3, sIL-1R4, and IL-18BP negatively correlated with cognitive impairment. A significant elevation of circulating sIL-1R2 and free IL-18, not present in SMC, is characteristic of MCI and disappears in AD, making them additional interesting markers for evaluating progression from MCI to AD.

Keywords: Alzheimer’s disease; Cytokines; IL-1 family; Inflammation; Mild cognitive impairment; Receptors; Subjective memory complaints.

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Conflict of interest statement

Ethics approval and consent to participate

This study was conducted in accordance with ethical principles stated in the Declaration of Helsinki, following approved national and international guidelines for human research. The study was reviewed and approved by the Ethics Committee of University of Molise (reference number 26119_II/1–22/10/2009). All participants or their caregivers signed a written informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

**Fig. 1**
IL-1 ligands and soluble receptors in serum of patients with Alzheimer’s disease. The circulating levels of ligands and soluble receptors of the factors of the IL-1 sub-system were assessed in serum of normal healthy subjects (NHS) in comparison with those detected in serum of patients with subjective memory complaints (SMC), mild cognitive impairment (MCI), and patients with Alzheimer’s disease (AD). The factors tested are IL-1α (upper left), IL-1β (upper right), IL-1Ra (middle left), sIL-1R1 (middle right, sIL-1R2 (lower left), and sIL-1R3 (lower right). Statistically significant differences are indicated. All other comparisons are statistically not significant

**Fig. 2**
IL-18 and IL-18BP in serum of patients with Alzheimer’s disease. The circulating levels of ligands and soluble receptors of the factors of the IL-18 sub-system were assessed in serum of normal healthy subjects (NHS) in comparison with those detected in serum of patients with subjective memory complaints (SMC), mild cognitive impairment (MCI), and patients with Alzheimer’s disease (AD). The factors tested are IL-18 (upper panel) and IL-18BP (middle panel). In the lower panel are reported the values of free IL-18, calculated from the quantitative values of IL-18 and IL-18BP. Statistically significant differences are indicated. All other comparisons are statistically not significant

**Fig. 3**
IL-33 and soluble receptor in serum of patients with Alzheimer’s disease. The circulating levels of ligands and soluble receptors of the factors of the IL-33 sub-system were assessed in serum of normal healthy subjects (NHS) in comparison with those detected in serum of patients with subjective memory complaints (SMC), mild cognitive impairment (MCI), and patients with Alzheimer’s disease (AD). The factors tested are IL-33 (upper panel) and sIL-1R4 (lower panel). Please note that the third component of the sub-system, the soluble accessory receptor chain sIL-1R3, is already reported in Fig. 1, as it is common to both the IL-1 and the IL-33 sub-systems. Statistically significant differences are indicated. All other comparisons are statistically not significant

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