Mitochondrial apoptosis and inflammasome activation
Mitochondrial apoptosis and inflammasome activation is a Research Project for the Cell Death and Inflammatory Signalling Research Group, under the Centre for Innate Immunity and Infectious Diseases.
Macrophages are innate immune cells that detect environmental, pathogen or host cellular danger molecules, and initiate appropriate immune responses. We have recently discovered that targeting pro-survival proteins BCL-XL and MCL-1 in macrophages induces apoptosis to clear microbial infection (Speir M et al. Nature Microbiology 2016) and also triggers inflammation via activation of the NOD-like receptor 3 (NLRP3) inflammasome and Interleukin-1beta (Vince JE et al. Cell Reports 2018). This project aims to define novel regulators of this pathway and investigate how these proteins alter pathogen clearance (Deo P et al. Nature Microbiology 2020). This project will use our novel gene knockout macrophages and specific targeted drugs, as well as a range of cell biology and biochemical/molecular approaches (e.g. inflammasome/cell death assays, ELISA, Western blotting, Q-PCR, over-expression systems, CRISPR Cas9 gene editing, infectious preclinical models).
Collaborators: Richard Ferrero (Hudson Institute), James Vince, Marco Herold, David Huang (WEHI), Thomas Naderer, Benjamin Kile (Monash University), Kate Stacey (UQ)
Deo P, Chow SH, Han M-L, Speir M, Huang C, Schittenhelm RB, Dhital S, Emery J, Li J, Kile BT, Vince JE#, Lawlor KE#, Naderer T (2020) Mitochondrial dysfunction caused by Gram negative bacterial outer membranes vesicles activates intrinsic apoptosis and inflammation. Nature Microbiology doi: 10.1038/s41564-020-0773-2
Schenk RL, Gangoda L, Lawlor KE, O’Reilly L, Strasser A, Herold M (2020) The Pro-Survival BCL-2 Family Member A1 Delays Spontaneous and FAS Ligand-Induced Apoptosis of Activated Neutrophils. Cell Death Disease 11(6):474
Vince JE*, De Nardo D, Gao W, Vince AJ, Hall C, McArthur K, Simpson D, Vijayaraj S, Lindqvist LM, Bouillet P, Rizzacasa M, Man SM, Silke J, Masters SL, Lessene G, Huang DCS, Gray DHD, Kile BT, Shao F, Lawlor KE* (2018) The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1 Activation. Cell Reports 25(9):2339-2353
Speir M, Lawlor KE, Glaser SP, Abraham G, Chow S, Vogrin A, Schulze KE, Schuelein R, O’Reilly LA, Mason K, Hartland EL, Lithgow T, Strasser A, Lessene G, Huang DC, Vince JE*†, Naderer T*† (2016) Eliminating Legionella by inhibiting BCL-XL to inhibit apoptosis. Nature Microbiology 1: Article 15034
Allam R*, Lawlor KE*, Yu EC, Mildenhall AL, Moujalled DM, Lewis RS, Ke F, Mason KD, White MJ, Stacey KJ, Strasser A, Alexander W, Kile BT, Vaux DL, Vince JE (2014) Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Reports 15(9):982-990. *co-first authors