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Integrated NLRP3, AIM2, NLRC4, Pyrin inflammasome activation and assembly drive PANoptosis

Cellular & Molecular Immunology volume 20, pages 1513–1526 (2023)Cite this article

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Abstract

Inflammasomes are important sentinels of innate immune defense; they sense pathogens and induce the cell death of infected cells, playing key roles in inflammation, development, and cancer. Several inflammasome sensors detect and respond to specific pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively) by forming a multiprotein complex with the adapters ASC and caspase-1. During disease, cells are exposed to several PAMPs and DAMPs, leading to the concerted activation of multiple inflammasomes. However, the molecular mechanisms that integrate multiple inflammasome sensors to facilitate optimal host defense remain unknown. Here, we discovered that simultaneous inflammasome activation by multiple ligands triggered multiple types of programmed inflammatory cell death, and these effects could not be mimicked by treatment with a pure ligand of any single inflammasome. Furthermore, NLRP3, AIM2, NLRC4, and Pyrin were determined to be members of a large multiprotein complex, along with ASC, caspase-1, caspase-8, and RIPK3, and this complex drove PANoptosis. Furthermore, this multiprotein complex was released into the extracellular space and retained as multiple inflammasomes. Multiple extracellular inflammasome particles could induce inflammation after their engulfment by neighboring macrophages. Collectively, our findings define a previously unknown regulatory connection and molecular interaction between inflammasome sensors, which drives the assembly of a multiprotein complex that includes multiple inflammasome sensors and cell death regulators. The discovery of critical interactions among NLRP3, AIM2, NLRC4, and Pyrin represents a new paradigm in understanding the functions of these molecules in innate immunity and inflammasome biology as well as identifying new therapeutic targets for NLRP3-, AIM2-, NLRC4- and Pyrin-mediated diseases.

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Acknowledgements

We thank Rajendra Karki (Seoul National University) and the members of the Lee lab (Viral Immunology Lab) for their helpful comments and suggestions. We thank Man-Seong Park (Korea University) for the gift of the influenza A virus (PR8) and Tae-Hyuk Kwon (UNIST) for the gift of the iBMDMs. We also thank Atsushi Kawaguchi (University of Tsukuba) for the gift of the MDCK cells.

Funding

This research was supported by the National Research Foundation of Korea (NRF) grant that was funded by the Korean government (MSIT) (2022R1C1C1007544 to SL), by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) that was funded by the Ministry of Health & Welfare, Republic of Korea (HV22C015600 to SL), by grants from the National Institute of Health, Republic of Korea (2022-NI-072-00 to SL), by the Institute for Basic Science (IBS), Republic of Korea (IBS-R801-D9-A09 to SL), by a research fund from Ulsan National Institute of Science & Technology (UNIST) (1.220112.01, 1.220107.01 to SL), by a grant from Yuhan Corporation (SL), by the National Research Foundation of Korea (NRF) and the Center for Women In Science, Engineering and Technology (WISET) grant that was funded by the Ministry of Science and ICT (MSIT) under the Program for Returners into R&D (to JL).

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  1. These authors contributed equally: SuHyeon Oh, Jihye Lee.

Authors and Affiliations

  1. Department of Biological Science, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea

    SuHyeon Oh, Jihye Lee, Jueun Oh, Gyoengju Yu & SangJoon Lee

  2. Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea

    Haesun Ryu & Daesik Kim

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SL conceptualized the study; SO, JL, and SL designed the methodology; SO, JL, JO, GY, HK, DK, and SL performed the experiments; SO, JL, and SL conducted the analysis; SO and SL wrote the manuscript; SL acquired the funding and provided overall supervision.

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Oh, S., Lee, J., Oh, J. et al. Integrated NLRP3, AIM2, NLRC4, Pyrin inflammasome activation and assembly drive PANoptosis. Cell Mol Immunol 20, 1513–1526 (2023). https://doi.org/10.1038/s41423-023-01107-9

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