Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity–independent pyroptosis, apoptosis, necroptosis, and inflammatory disease
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- R.K. Subbarao Malireddi
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
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- Prajwal Gurung
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
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- Sannula Kesavardhana
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
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- Parimal Samir
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
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- Amanda Burton
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
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- Harisankeerth Mummareddy
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
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- Peter Vogel
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 3
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- Stephane Pelletier
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
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- Sandeepta Burgula
- Department of Microbiology, Osmania University, Hyderabad, Telangana, India 4
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- Thirumala-Devi Kanneganti
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
抄録
<jats:p>RIPK1 kinase activity has been shown to be essential to driving pyroptosis, apoptosis, and necroptosis. However, here we show a kinase activity–independent role for RIPK1 in these processes using a model of TLR priming in a TAK1-deficient setting to mimic pathogen-induced priming and inhibition. TLR priming of TAK1-deficient macrophages triggered inflammasome activation, including the activation of caspase-8 and gasdermin D, and the recruitment of NLRP3 and ASC into a novel RIPK1 kinase activity–independent cell death complex to drive pyroptosis and apoptosis. Furthermore, we found fully functional RIPK1 kinase activity–independent necroptosis driven by the RIPK3–MLKL pathway in TAK1-deficient macrophages. In vivo, TAK1 inactivation resulted in RIPK3–caspase-8 signaling axis–driven myeloid proliferation and a severe sepsis-like syndrome. Overall, our study highlights a previously unknown mechanism for RIPK1 kinase activity–independent inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis) that could be targeted for treatment of TAK1-associated myeloid proliferation and sepsis.</jats:p>
収録刊行物
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- Journal of Experimental Medicine
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Journal of Experimental Medicine 217 (3), e20191644-, 2019-12-23
Rockefeller University Press