NINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress

Joo-Hui Han, Rajendra Karki, R. K. Subbarao Malireddi, Raghvendra Mall, Roman Sarkar, Bhesh Raj Sharma, Jonathon Klein, Harmut Berns, Harshan Pisharath, Shondra M. Pruett-Miller, Sung-Jin Bae and Thirumala-Devi Kanneganti ()
Additional contact information
Joo-Hui Han: St. Jude Children’s Research Hospital
Rajendra Karki: St. Jude Children’s Research Hospital
R. K. Subbarao Malireddi: St. Jude Children’s Research Hospital
Raghvendra Mall: St. Jude Children’s Research Hospital
Roman Sarkar: St. Jude Children’s Research Hospital
Bhesh Raj Sharma: St. Jude Children’s Research Hospital
Jonathon Klein: Center for Advanced Genome Engineering, St Jude Children’s Research Hospital
Harmut Berns: Center for Advanced Genome Engineering, St Jude Children’s Research Hospital
Harshan Pisharath: Animal Resources Center, St Jude Children’s Research Hospital
Shondra M. Pruett-Miller: Center for Advanced Genome Engineering, St Jude Children’s Research Hospital
Sung-Jin Bae: Kosin University
Thirumala-Devi Kanneganti: St. Jude Children’s Research Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Innate immunity provides the first line of defense through multiple mechanisms, including pyrogen production and cell death. While elevated body temperature during infection is beneficial to clear pathogens, heat stress (HS) can lead to inflammation and pathology. Links between pathogen exposure, HS, cytokine release, and inflammation have been observed, but fundamental innate immune mechanisms driving pathology during pathogen exposure and HS remain unclear. Here, we use multiple genetic approaches to elucidate innate immune pathways in infection or LPS and HS models. Our results show that bacteria and LPS robustly increase inflammatory cell death during HS that is dependent on caspase-1, caspase-11, caspase-8, and RIPK3 through the PANoptosis pathway. Caspase-7 also contributes to PANoptosis in this context. Furthermore, NINJ1 is an important executioner of this cell death to release inflammatory molecules, independent of other pore-forming executioner proteins, gasdermin D, gasdermin E, and MLKL. In an in vivo HS model, mortality is reduced by deleting NINJ1 and fully rescued by deleting key PANoptosis molecules. Our findings suggest that therapeutic strategies blocking NINJ1 or its upstream regulators to prevent PANoptosis may reduce the release of inflammatory mediators and benefit patients.

Date: 2024
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DOI: 10.1038/s41467-024-45466-x

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