The NLRP3 inflammasome is an immunological sensor that detects multiple microbial- and host-derived signals. Activation is a two-step process, requiring an initial priming stimulus followed by a second activation signal, but precisely how different priming stimuli affect NLRP3 signalling is unclear. While priming is closely associated with NLRP3, the impact of priming on other inflammasomes such as NLRP1 has not been characterised. Caspase-recruitment domain-only proteins (COPs) and pyrin domain-only proteins (POPs) also regulate inflammasome activation, but our knowledge of their contribution to inflammasome priming is currently incomplete.
Using primary mouse and human macrophages and human induced pluripotent stem cell (iPSC)-derived macrophages, we investigated the effectiveness of different priming stimuli on inflammasome activation and COP/POP expression. The role of type I interferon (IFN) signalling was characterised using the JAK inhibitor Tofacitinib and Ifnar1-/- macrophages.
Bacterial and viral stimuli induced transcription-dependent and -independent priming of NLRP3, respectively, but all stimuli triggered formation of ASC specks, indicating inflammasome formation. In contrast, long-term LPS priming limited NLRP3 and NLRP1 activation which was dependent on type I IFN signalling. Microbial stimuli and IFN signalling also increased COP/POP expression, suggesting COPs and POPs potentially act in a negative feedback mechanism to prevent excessive inflammasome activity. In addition, priming with microbial and sterile stimuli triggered NLRP3 inflammasome activation in iPSC-derived macrophages, similar to observations in HMDM, indicating that they are a useful model to study inflammasome regulation.
These findings highlight the importance of priming in inflammasome regulation and the role of IFN signalling, which drives tolerance to long-term LPS priming.

The NLRP3 inflammasome is an immunological sensor that detects multiple microbial- and host-derived signals. Activation is a two-step process, requiring an initial priming stimulus followed by a second activation signal, but precisely how different priming stimuli affect NLRP3 signalling is unclear. While priming is closely associated with NLRP3, the impact of priming on other inflammasomes such as NLRP1 has not been characterised. Caspase-recruitment domain-only proteins (COPs) and pyrin domain-only proteins (POPs) also regulate inflammasome activation, but our knowledge of their contribution to inflammasome priming is currently incomplete.
Using primary mouse and human macrophages and human induced pluripotent stem cell (iPSC)-derived macrophages, we investigated the effectiveness of different priming stimuli on inflammasome activation and COP/POP expression. The role of type I interferon (IFN) signalling was characterised using the JAK inhibitor Tofacitinib and _Ifnar1_-/- macrophages.
Bacterial and viral stimuli induced transcription-dependent and -independent priming of NLRP3, respectively, but all stimuli triggered formation of ASC specks, indicating inflammasome formation. In contrast, long-term LPS priming limited NLRP3 and NLRP1 activation which was dependent on type I IFN signalling. Microbial stimuli and IFN signalling also increased COP/POP expression, suggesting COPs and POPs potentially act in a negative feedback mechanism to prevent excessive inflammasome activity. In addition, priming with microbial and sterile stimuli triggered NLRP3 inflammasome activation in iPSC-derived macrophages, similar to observations in HMDM, indicating that they are a useful model to study inflammasome regulation.
These findings highlight the importance of priming in inflammasome regulation and the role of IFN signalling, which drives tolerance to long-term LPS priming.

Priming is a fundamental mechanism of inflammasome regulation in myeloid cells

Exploring the intricacies of host-pathogen communication is vital in order to understand why
some microbes persist within a host, while others are effectively cleared. As such,
host-pathogen communication is an urgent area of research underpinning human health
and disease, especially given the emerging concerns of antibiotic resistance.
Understanding host-pathogen pathways requires intricate knowledge in the fields of both
microbiology and immunology.

Living in a world of specialists, where scientists sometimes invest their whole career
studying one organism, a specific pathway or a protein, multidisciplinary discussions of
host-pathogen interactions are highly needed. This international conference will provide
such a forum for scientific exchange at the highest level, between scientists from different
research areas related to host-pathogen interactions, with the aim to trigger fruitful
collaborations addressing the urgent questions in the field.

This meeting has an additional special focus of bringing researchers from Ireland, Denmark
and Israel together to learn about cutting edge biology and form new collaborations.
Thus, the conference will be a showcase for the exciting and original research emanating
from these three small but innovative countries.