The lab studies non-apoptotic forms of cell death including pyroptosis and necroptosis. In particular, we investigate how pathogen recognition and hematopoietic stress activates these cell death pathways in hematopoietic stem and progenitor cells to induce cytopenia, immunosuppression and in some cases bone marrow failure. We also study the contribution of cell death to cytopenia in patients with septic shock. This persistent cytopenia commonly affects myeloid, lymphoid and erythroid lineages resulting in immunosuppression, and is a strong predictor of morbidity and mortality.
A second major focus is the role of necroptosis in the viability of hematopoietic progenitors and the self-renewal capacity of HSC during hematopoietic stress induced by transplant. Bone marrow transplantation is a major treatment modality for cancer patients who have undergone chemotherapy. However, engraftment of hematopoietic stem cells takes several weeks, while a return to full immunocompetence takes up to 2 years, leaving patients vulnerable to life-threatening infection. This research investigates strategies to support hematopoietic stem cell viability.
1. BA Croker, D Metcalf, L Robb, W Wei, S Mifsud, L DiRago, LA Cluse, KD Sutherland, L Hartley, E Williams, JG Zhang, DJ Hilton, NA Nicola, WS Alexander, AW Roberts. SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis. Immunity 2004, 20, 153-165.
2. BA Croker, K Crozat, M Berger, Y Xia, S Sovath, I Eleftherianos, JL Imler, B Beutler. ATP-sensitive potassium channels mediate survival during infection in mammals and insects. Nature Genetics 2007, Dec 39: 1453-60.
3. SL Masters, LA Mielke, AL Cornish, CE Sutton, J O’Donnell, LH Cengia, AW Roberts, IP Wicks, KHG Mills, BA Croker. Regulation of IL-1β by IFNγ is species-specific, limited by SOCS1 and influences IL-17 production. EMBO reports 2010, 11:640-6.
4. BA Croker, RS Lewis, JJ Babon, JD Mintern, DE Jenne, D Metcalf, JG Zhang, LH Cengia, JA O’Donnell, AW Roberts. Neutrophils require SHP1 to regulate IL-1β production and prevent inflammatory skin disease. J Immunology 2011 186:1131-9.
5. BA Croker, JA O’Donnell, CJ Nowell, D Metcalf, G Dewson, KJ Campbell, KL Rogers, Y Hu, GK Smyth, JG Zhang, M White, K Lackovic, LH Cengia, LA O’Reilly, P Bouillet, S Cory, A Strasser, AW Roberts. Fas-mediated neutrophil apoptosis is accelerated by Bid, Bak and Bax and inhibited by Bcl-2 and Mcl-1. PNAS 2011, 108:13135-40.
6. SL Masters, M Gerlic, D Metcalf, S Preston, M Pellegrini, JA O’Donnell, K McArthur, TM Baldwin, S Chevrier, CJ Nowell, LH Cengia, KJ Henley, JE Collinge, DL Kastner, L Feigenbaum, DJ Hilton, WS Alexander, BT Kile, BA Croker. NLRP1 activation induces pyroptosis of hematopoietic progenitor cells. Immunity 2012, 37: 1009.
7. JA Rickard, JA O'Donnell, JM Evans, N Lalaoui, AR Poh, T Rogers, JE Vince, KE Lawlor, RL Ninnis, H Anderton, C Hall, SK Spall, TJ Phesse, HE Abud, LH Cengia, J Corbin, S Mifsud, L Di Rago, D Metcalf, AW Roberts, WS Alexander, JM Murphy, PG Ekert, SL Masters, *BA Croker, *M Gerlic, *J Silke. RIPK1 regulates RIPK3-MLKL driven systemic inflammation and emergency hematopoiesis. Cell 2014, 157: 1175-1188. *contributed equally
Last Update: 6/11/2014