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Cation Channels as Regulators and Effectors of NLRP3 Inflammasome Signaling and IL-1 Beta Secretion

Katsnelson, Michael Alexander
http://rave.ohiolink.edu/etdc/view?acc_num=case1441057983

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Pathology.
IL-1 beta is a pro-inflammatory cytokine that plays a crucial role in the systemic response to infection. Dysregulated IL-1 beta signaling is involved in multiple genetically inherited, autoimmune, and chronic inflammatory diseases. IL-1 beta is expressed as a pro-cytokine which must be processed by cellular proteases into the mature form to mediate signaling. Several Pattern Recognition Receptors (PRRs) are capable of inducing processing of pro-IL-1 beta by the protease caspase-1 via stimulating the formation of cytosolic macromolecular complexes called inflammasomes. NLRP3 is a unique inflammasome-forming PRR because it senses a wide variety of cellular stressors including bacterial pore forming toxins (which alter cytosolic cation homeostasis) and crystalline particulates (which disrupt lysosome integrity). Although the ligand of NLRP3 remains unknown, we and others have suggested that efflux of cytosolic K+ is the common upstream event mediating NLRP3 inflammasome assembly. Several recent studies have utilized pharmacologic approaches to implicate Ca2+ signaling in NLRP3 activation. In the first part of this dissertation, I hypothesized that increases in cytosolic [Ca2+] act synergistically with efflux of cytosolic K+ to stimulate NLRP3 inflammasome complex assembly. However, we observed that increases in cytosolic [Ca2+] are not required for activation of NLRP3 inflammasome signaling in response to strong K+ efflux agonists (the K+ ionophore nigericin and opening of the P2X7 cation channel by extracellular ATP) and inhibit NLRP3 inflammasome signaling in response to lysosome permeabilization. I also sought to elucidate the mechanism by which lysosome destabilization stimulates NLRP3 inflammasome assembly. In the second part of this dissertation, I hypothesized that lysosome destabilizers activate NLRP3 inflammasome signaling by causing the opening of channels/pores in the plasma membrane which then mediate efflux of cytosolic K+. I found that collapse of lysosome integrity causes a change in permeability of the plasma membrane to K+ and Ca2+ upstream of inflammasome activation. This disruption of cation homeostasis then drives NLRP3 inflammasome signaling as well as an inflammasome-independent necrotic cell death which is dependent upon influx of extracellular Ca2+. My studies have forged a link between two different forms of cell stress that are both sensed by NLRP3: changes in cytosolic cation homeostasis and lysosome permeabilization.
George Dubyak (Advisor)
183 p.
Immunology
innate immunity; dendritic cells; NLRP3 inflammasome; cytosolic cation levels; lysosome

Recommended Citations

Citations

  • Katsnelson, M. A. (2015). Cation Channels as Regulators and Effectors of NLRP3 Inflammasome Signaling and IL-1 Beta Secretion [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1441057983

    APA Style (7th edition)

  • Katsnelson, Michael. Cation Channels as Regulators and Effectors of NLRP3 Inflammasome Signaling and IL-1 Beta Secretion. 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1441057983.

    MLA Style (8th edition)

  • Katsnelson, Michael. "Cation Channels as Regulators and Effectors of NLRP3 Inflammasome Signaling and IL-1 Beta Secretion." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1441057983

    Chicago Manual of Style (17th edition)

case1441057983
639
© 2015, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.