PhD Scientific Days 2021

MO_I_L: Molecular Sciences I. Lectures

The Type I Interferon-dependent Regulation of the NLRP3 Pathway in Human Plasmacytoid Dendritic Cells

Text of the abstract

Generally reciprocal antagonistic effects can be observed between the antiviral type I interferon (IFN) and the antibacterial IL-1β pathways, which not only affect antimicrobial responses, but also shape the immune responses in autoimmune diseases. Plasmacytoid dendritic cells (pDCs) as professional type I IFN producing cells are the major coordinators of antiviral immune responses. However, the NLRP3-dependent IL-1β secretory pathway in pDCs is still unexplored.
In this study, our aim was to investigate the functional activity of the IL-1β pathway in human pDCs and to examine the possible interactions between type I IFN and IL-1β pathways.
Human pDCs were treated with distinct Toll-like receptor (TLR) agonists, which differ in their type I IFN inducing capacity, in the presence or absence of IFN-α cytokine, then the activity of the NLRP3 pathway was analyzed by Q-PCR, western blot, ELISA and flow cytometry.
We observed that the applied TLR9 agonists induced pro-IL-1β production in pDCs in a different manner. CpG-A, which is a strong type I IFN inducer, promoted pro-IL-1β production in pDCs to a lesser extent than CpG-B, which is a strong activator of the NF-κB pathway, but results only in a low IFN-α release. Nigericin-elicited mature, cleaved IL-1β secretion could only be detected after CpG-B pre-treatment of pDCs. However, CpG-B treatment in the presence of IFN-α also resulted in lower IL-1β production in pDCs. In line with these results, we also detected significantly lower CpG-B-induced pro-IL-1β production in pDCs of patients with psoriasis compared to healthy individuals. Since psoriasis is associated with high IFN-α levels, these findings further suggest that type I IFNs may inhibit NLRP3 inflammasome activity in pDCs.
Our results show that the NLRP3-dependent IL-1β secretory pathway is inducible in human pDCs; however, it can be inhibited by activating the type I IFN pathway. Thus, the IL-1β-mediated responses of pDCs may prevail in inflammations, in which the type I IFN pathway is not dominant.
Funding: NKFIH FK 128294, GINOP-2.3.2-15-2016-00050 and EFOP-3.6.3-VEKOP-16-2017-00009 projects, ÚNKP-20-05-DE-3 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund and the János Bolyai Research Scholarship from the Hungarian Academy of Sciences.

University and Doctoral School

Debrecen University Faculty of Medicine, Doctoral School of Molecular Cell and Immunobiology