Laquinimod dampens IL-1β signaling and Th17-polarizing capacity of monocytes in patients with MS
Objective To assess the impact of laquinimod treatment on monocytes and to investigate the underlying immunomodulatory mechanisms in MS. - Methods In this cross-sectional study, we performed in vivo and in vitro analyses of cluster of differentiation (CD14+) monocytes isolated from healthy donors (n...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2021
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| In: |
Neurology: Neuroimmunology & Neuroinflammation ; official journal of the American Academy of Neurology
Year: 2020, Volume: 8, Issue: 1, Pages: 1-10 |
| ISSN: | 2332-7812 |
| DOI: | 10.1212/NXI.0000000000000908 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1212/NXI.0000000000000908 Verlag, lizenzpflichtig, Volltext: https://nn.neurology.org/content/8/1/e908 
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| Author Notes: | Sinah Engel, MD, Valérie Jolivel, PhD, Stefan H.-P. Kraus, PhD, Morad Zayoud, MD, Karolina Rosenfeld, Hayrettin Tumani, MD, Roberto Furlan, MD, PhD, Florian C. Kurschus, PhD, Ari Waisman, PhD, and Felix Luessi, MD |
| Summary: | Objective To assess the impact of laquinimod treatment on monocytes and to investigate the underlying immunomodulatory mechanisms in MS. - Methods In this cross-sectional study, we performed in vivo and in vitro analyses of cluster of differentiation (CD14+) monocytes isolated from healthy donors (n = 15), untreated (n = 13), and laquinimod-treated patients with MS (n = 14). Their frequency and the expression of surface activation markers were assessed by flow cytometry and the viability by calcein staining. Cytokine concentrations in the supernatants of lipopolysaccharide (LPS)-stimulated monocytes were determined by flow cytometry. The messenger ribonucleic acid (mRNA) expression level of genes involved in cytokine expression was measured by quantitative PCR. The LPS-mediated nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) activation was determined by the quantification of the phosphorylation level of the p65 subunit. Laquinimod-treated monocytes were cocultured with CD4+ T cells, and the resulting cytokine production was analyzed by flow cytometry after intracellular cytokine staining. The interleukin (IL)-17A concentration of the supernatant was assessed by ELISA. - Results Laquinimod did not alter the frequency or viability of circulating monocytes, but led to an upregulation of CD86 expression. LPS-stimulated monocytes of laquinimod-treated patients with MS secreted less IL-1β following a downregulation of IL-1β gene expression. Phosphorylation levels of the NF-κB p65 subunit were reduced after laquinimod treatment, indicating a laquinimod-associated inhibition of the NF-κB pathway. T cells primed with laquinimod-treated monocytes differentiated significantly less into IL-17A-producing T helper (Th)-17 cells. - Conclusions Our findings suggest that inhibited NF-κB signaling and downregulation of IL-1β expression in monocytes contributes to the immunomodulatory effects of laquinimod and that the impairment of Th17 polarization might mediate its disease-modifying activity in MS. |
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| Item Description: | First published November 17, 2020 Gesehen am 02.03.2021 |
| Physical Description: | Online Resource |
| ISSN: | 2332-7812 |
| DOI: | 10.1212/NXI.0000000000000908 |