- PhD University of Pittsburgh, 2006
- BS University of Minnesota Duluth, 2001
Inflammation: macrophage responses to pore-forming toxins
Inflammation is a crucial component of many diseases, regardless of whether they are caused by autoimmunity like lupus, pathogenic microbes like Streptococcus pyogenes, tumors, or even particles and chemicals. Inflammation is also necessary to develop robust responses to vaccines. This inflammation depends on the response of macrophages and other innate immune cells to pathogenic conditions.
The research in my lab aims to elucidate novel mechanisms of inflammation by studying the interplay and downstream effects of bacterial pore-forming toxins, which trigger inflammation, on macrophages. Streptolysin O is an archetypal pore-forming toxin that can directly lyse cells. Interestingly, macrophages can withstand high doses of toxin. At these sublytic concentrations, macrophages resist the damage and execute a pro-inflammatory pathway. Understanding what mechanisms are required for damage resistance will help us regulate the inflammatory response, as well as apply that knowledge to other diseases directly related to membrane damage, such as muscular dystrophies and septic cardiomyopathy.
A second aspect of the inflammatory response is the mechanism through which macrophages alert the rest of the immune system and elaborate the inflammatory response. To accomplish this, macrophages utilize a complex called the inflammasome to promote cytokine processing and release. In addition to cytokine processing and release, the macropahges also commit suicide via the pyroptotic cell death pathway. Elucidating how macrophages switch from incredible resistance to membrane damage induced by SLO and other agents to dismantling this resistance and tearing their own membranes apart will help us understand the fundamental cell death and repair mechanisms that lie at the heart of inflammation.
Finally, the inflammatory response in lupus is caused by auto-antibodies to targets like double-stranded DNA. Macrophages secrete the endonuclease Dnase1L3 that degrades chromatin and eliminates autoantibody targets. We are interested in the structure-function of Dnase1L3 and the mechanism by which it degrades chromatin.
- Thapa, R., Ray, S. and P.A. Keyel. (2020). Interaction of Macrophages and Cholesterol-Dependent Cytolysins: The Impact on Immune Response and Cellular Survival. Toxins (Basel), 12(9):E531
- Ray, S., Thapa, R. and P.A. Keyel. (2018). Multiple Parameters Beyond Lipid Binding Affinity Drive Cytotoxicity of Cholesterol-Dependent Cytolysins. Toxins (Basel), 11(1): 1
- Bhattacharjee, P. and P.A. Keyel. (2018). Cholesterol-dependent cytolysins impair pro-inflammatory macrophage responses. Sci. Rep. 8(1): 6458
Romero, M., Keyel, M., Shi, G., Bhattacharjee, P., Roth, R., Heuser, J.E., and P.A. Keyel. (2017). Intrinsic repair protects cells from pore-forming toxins by microvesicle shedding. Cell Death Differ, 24(5):798-808.
Shi, G., Abbott, K.N., Wu, W., Salter, R.D., and P.A. Keyel. (2017). Dnase1L3 Regulates Inflammasome-Dependent Cytokine Secretion. Front. Immunol. 8:522
- Keyel, P.A., Roth, R., Yokoyama, W.M., Heuser, J.E. and R.D. Salter. (2013) Reduction of SLO Pore-forming Activity Enhances Inflammasome Activation. Toxins (Basel), 5(6):1105-1118. PMCID: PMC3717772.
- Keyel, P.A., Heid, M.E., Watkins, S.C. and R.D. Salter. (2012) Visualization of Bacterial Toxin Induced Responses Using Live Cell Fluorescence Microscopy. J Vis Exp, Oct 1(68): 4227.
- Keyel, P.A., Tkacheva, O.A., Larregina, A.T. and R.D. Salter. (2012) Coordinate Stimulation of Macrophages by Microparticles and TLR Ligands Induces Foam Cell Formation. J Immunol, 189(9):4621-4629. PMCID: PMC3478499
- Keyel, P.A., Loultcheva, L., Roth, R., Salter, R.D., Watkins, S.C., Yokoyama, W.M. and J.E. Heuser. (2011) Streptolysin O Clearance Via Sequestration Into Blebs That Bud Passively From the Plasma Membrane. J. Cell Sci., 124(14): 2414-2423. PMCID: PMC3124372
- Cooper, M.A., Elliott, J.M., Keyel, P.A., Yang, L., Carrero, J.A., and W.M. Yokoyama. (2009) Cytokine-Induced Memory-Like Natural Killer Cells. PNAS, 106(6):1915-1919. PMCID: PMC2644138
- Keyel, P.A., Thieman, J.R., Roth, R., Erkan, E., Everett, E.T., Watkins, S.C., Heuser, J.H., and L.M. Traub. (2008) The AP-2 Adaptor Beta2 Appendage Scaffolds Alternate Cargo Endocytosis. Mol Biol. Cell., 19(12): 5309-2326. PMCID: PMC2592659
- Tripathy, S.K., Keyel, P.A., Yang, L., Pingel, J.T., Cheng, T.P., Schneeberger, A. and W.M. Yokoyama. (2008) Continuous Engagement of a Self-MHC-specific Activation Receptors Induces NK Cell Tolerance. J. Exp. Med., 205(8): 1829-1841. PMCID: PMC2525593