Cell Death and Inflammatory Signalling Research Group
Research Group Head
The Cell Death and Inflammatory Signalling group aims to identify new molecules that regulate cell death and inflammatory signalling. We also seek to establish whether cell death signalling can be inhibited therapeutically to treat inflammatory disease or triggered to promote antimicrobial responses.
Dr Lawlor and her team investigate the cross-talk between programmed cell death and inflammatory signalling pathways in disease. In particular, the laboratory studies how cell death induces activation of the NLRP3 inflammasome. Inflammasomes activate pro-inflammatory proteins Interleukin-1β (IL-1β) and IL-18 and induce a lytic form of cell death, called pyroptosis. This activity is critical for clearance of microbial organisms by the immune system. However, excess IL-1β activity can exacerbate rare hereditary autoinflammatory syndromes and common diseases, such as rheumatoid arthritis, type 2 diabetes and cancer.
The Lawlor group utilise a range of cellular and molecular biology methods and preclinical disease models.
- Role of Cell Death and pore forming proteins in Type 2 Diabetes
- Identifying mitochondrial factors that activate inflammatory signalling
- Mitochondrial apoptosis and inflammasome activation
- Defining regulators of cell death and inflammasome activation
Lawlor KE*, Feltham RL*, Yabal M*, Conos SA, Chen KW, Ziehe S, Graß C, Zhan Y, Nguyen TA, Hall C, Vince AJ, Chatfield SM, D’Silva DB, Pang KC, Schroder K, Silke J, Vaux DL, Jost PJ‡, Vince JE‡ *Joint first authors (2017) XIAP Loss Triggers RIPK3 and Caspase-8-Driven IL-1b activation and Cell Death as a Consequence of TLR-MyD88-induced cIAP1-TRAF2 degradation. Cell Reports 20: 668-682.
Conos SA, Chen KW, De Nardo D, Whitehead L, Hara H, Vaux DL, Nùñez G, Masters SL, Murphy JM, Schroder K, Lawlor KE*, Lindqvist LM*, Vince JE* *Joint senior authors (2017) Active MLKL triggers the NLRP3 inflammasome in a cell intrinsic manner. Proceedings of the National Academy of Sciences USA 114:E961-E969.
Lawlor KE, Khan N, Mildenhall A, Gerlic M, Croker BA, D’Cruz AA, Hall C, Spall S, Anderton H, Masters SL, Rashidi M, Wicks IP, Alexander WS, Mitsuuchi Y, Benetatos CA, Condon SM, Wong WW, Silke J*, Vaux DL* Vince JE* (2015) RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nature Communications 6:6282.
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 *Joint first authors (2014) Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Reports 15:982-990.
Lawlor KE, van Nieuwenhuijze A, Parker KL, Drake SF, Campbell IK, Smith SD, Vince JE, Strasser A, Wicks IP (2013) Bcl-2 overexpression ameliorates immune complex-mediated arthritis by altering FcγRIIb expression and monocyte homeostasis. Journal of Leukocyte Biology 93: 585-597.
Lawlor KE, Smith SD, van Nieuwenhuijze A, Huang DC, Wicks IP (2011) Evaluation of Bcl-2 antagonist ABT-737 in collagen-induced arthritis. Journal of Leukocyte Biology 90:819-829.
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-1b Activation. Cell Reports 25:2339-2353.