Laboratory of Innate Immunity and Cell Death Publication

PUBLICATION

NINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress
Author
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 , Thirumala-Devi Kanneganti
Journal
Nature Communications
Status
2024
Vol
15(1)
Page
1739
Year
2024
File
80_2024_NINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress.pdf (3.9M) 13회 다운로드 DATE : 2024-02-29 15:52:24

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.

# equal contribution