Laquinimod dampens IL-1β signaling and Th17-polarizing capacity of monocytes in patients with MS / 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

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..

Medienart:	E-Artikel

Erscheinungsjahr:	2021
Erschienen:	2021

Enthalten in:	Zur Gesamtaufnahme - volume:8
Enthalten in:	Neurology: Neuroimmunology & Neuroinflammation ; official journal of the American Academy of Neurology - 8(2021,1) Artikel-Nummer e908, 10 Seiten

Sprache:	Englisch

Weiterer Titel:	Laquinimod dampens IL-one beta signaling and Th seventeen-polarizing capacity of monocytes in patients with MS

Beteiligte Personen:	Engel, Sinah, 1990- [VerfasserIn] Jolivel, Valérie [VerfasserIn] Kraus, Stefan H.-P. [VerfasserIn] Zayoud, Morad [VerfasserIn] Rosenfeld, Karolina [VerfasserIn] Tumani, Hayrettin [VerfasserIn] Furlan, Roberto [VerfasserIn] Kurschus, Florian, 1969- [VerfasserIn] Waisman, Ari [VerfasserIn] Luessi, Felix [VerfasserIn]

Links:	Volltext [lizenzpflichtig] Volltext [lizenzpflichtig]

Anmerkungen:	First published November 17, 2020 Gesehen am 02.03.2021

doi:	10.1212/NXI.0000000000000908

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	1750097273