Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity–independent pyroptosis, apoptosis, necroptosis, and inflammatory disease

DOI PDF 1 Citations
  • R.K. Subbarao Malireddi
    Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
  • Prajwal Gurung
    Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
  • Sannula Kesavardhana
    Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
  • Parimal Samir
    Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
  • Amanda Burton
    Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
  • Harisankeerth Mummareddy
    Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
  • Peter Vogel
    Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 3
  • Stephane Pelletier
    Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1
  • Sandeepta Burgula
    Department of Microbiology, Osmania University, Hyderabad, Telangana, India 4
  • Thirumala-Devi Kanneganti
    Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 1

Abstract

<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>

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