Gasdermin D promotes hyperinfLammation by triggering necroptosis in the presence of mitochondrial stress Academic Article uri icon


  • Abstract Human genetic variants associated with mitochondrial dysfunction have been linked to chronic inflammatory diseases as well as susceptibility to infection. However, the mechanistic impact that these variants have on the immune system is poorly understood. We have discovered that macrophages harboring the common Parkinsons disease associated variant, Lrrk2G2019S are more prone to cell death in response to both Mycobacterium tuberculosis (Mtb) infection and AIM2 inflammasome activation. Unexpectedly, the enhanced cell death in Lrrk2G2019S macrophages is driven by increased susceptibility to gasdermin D (GSDMD)-mediated mitochondrial pore formation, which releases accumulated mitochondrial ROS and pushes Lrrk2G2019S cells to undergo RIPK3-mediated necroptosis. Consistent with elevated necroptotic cell death, infection of Lrrk2G2019S mice with Mtb elicits dramatic hyperinflammation and exacerbated pathogenesis via enhanced neutrophil infiltration. Remarkably, expression of hLRRK2G2019S in Drosophila melanogaster recapitulates a similar phenotype, suggesting that Lrrk2G2019S plays an evolutionarily conserved role in regulating innate immunity. Our findings demonstrate that altered mitochondrial function can reprogram canonical innate immune and cell death pathways to elicit distinct immune outcomes, providing mechanistic insights into why mutations in LRRK2 are associated with susceptibility to chronic inflammatory and infectious diseases. Supported by grants from the Parkinson's Foundation (PF-FBS-1932), NIH (R01 AI125512), Michael J. Fox Foundation (grant 12185),and the Texas A&M Clinical Science and Translational Research (CSTR) Pilot Grant Program.

published proceedings


author list (cited authors)

  • Weindel, C. G., Zhao, X., Martinez, E., Bell, S. L., Vail, K. J., Coleman, A. K., ... Watson, R. O.

citation count

  • 0

complete list of authors

  • Weindel, Chi Gidley||Zhao, Xiao||Martinez, Eduardo||Bell, Samantha L||Vail, Krystal J||Coleman, Aja K||VanPortfliet, Jordyn J||Mabry, Cory J||Li, Pingwei||West, A Phillip||Karpac, Jason||Patrick, Kristin L||Watson, Robert O

publication date

  • May 2022