PhD Scientific Days 2022

Molecular Sciences I. (Poster discussion will take place in the Aula during the Coffee Break)

Investigating the NLRP3 Pathway Activity in Virus Exposed Human Plasmacytoid Dendritic Cells

Text of the abstract

Introduction: Viral infections are often associated with bacterial superinfections, which is partially the result of inhibitory interactions between the antiviral type I interferon (IFN) and the antibacterial NLRP3-dependent IL-1β pathways. These reciprocal antagonistic effects shape the immune responses against pathogens. Plasmacytoid dendritic cells (pDC), as professional type I IFN-producing cells are one of the most potent participants of antiviral immune responses. However, the NLRP3 pathway that determines the immune response to bacterial infections is still unexplored in these cells.
Aims: Thus, we aimed to investigate the interactions of type I IFN and NLRP3-dependent IL-1β pathways in human pDCs.
Methods: In our experiments, a human pDC cell line and primary pDCs were treated with synthetic activators, pathogenic bacteria (E. coli), RNA (VSV) and DNA (HSV) viruses. The NLRP3 pathway activity was monitored by western blot, ELISA, Q-PCR and flow cytometry. The bacterium-induced IL-1β response of pDCs was also determined in the presence of RNA and DNA viruses as well as in the presence of the cytokine IFN-α.
Results: Compared to viruses pathogenic bacteria were observed to induce NLRP3 activation in pDCs to a much larger extent. Furthermore, bacterium-induced IL-1β production can be inhibited in the presence of RNA and DNA viruses, presumably due to the inhibitory effects of virus-induced type I IFNs on the NLRP3-dependent IL-1β pathway. This is further proven by our finding that the presence of the cytokine IFN-α in the cell culture medium significantly reduced the IL-1β production of pDCs by inducing the expression of various NLRP3 pathway inhibitors such as cholesterol-25-hydroxylase, SOCS1 and COP1.
Conclusion: Our results show that antagonistic effects can be observed between the antiviral type I IFN and the antibacterial IL-1β pathways in human pDCs. Thus, the IL-1β-mediated immune responses of pDCs may prevail in inflammatory conditions in which the type I IFN pathway is not dominant.
Funding: NKFIH FK 128294, GINOP-2.3.2-15-2016-00050 projects, UNKP-21-05-DE-170, ÚNKP-21-3-II-DE-21 New National Excellence Program of the Ministry for Innovation and Technology managed by the National Research, Development and Innovation Office and the János Bolyai Research Scholarship from the Hungarian Academy of Sciences.