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Interleukin 1 Receptor1 signaling in Platelet Inflammatory responses Interleukin-1ß processing and secretion

Narayanan, Padmini

Abstract Details

2014, Doctor of Philosophy in Regulatory Biology, Cleveland State University, College of Sciences and Health Professions.
Anucleate platelets alter their transcriptome through stimulated splicing of intron and exon containing hnRNA e.g. Interleukin-1ß (IL-1ß), BCL-3. Platelet TLR4 activation upon Lipopolysaccharide (LPS) binding induces accumulation of spliced IL-1ß mRNA and IL-1ß laden microparticle shedding. Interleukin-1 Receptor 1 (IL-1R1) shares downstream signaling molecules with TLR-4, and its presence and possible role in platelet responses is unknown. Here I show that, platelets do express surface IL-R1 and is functional upon binding IL-1ß. Platelet IL-1R1 could recognize endogenous ligands as well observed through the in vivo accumulation of IL-1ß during clot formation in mouse models. Platelets are the primary source of this IL-1ß accumulation, dependent on post transcriptional processing events and translation of platelet IL-1ß mRNA. Proinflammatory IL-1ß is produced as a leader less proprotein and its mode of secretion remains opaque. This study demonstrates that IL-1ß is released in soluble form and also in association with plasma membrane shed microparticles and endo-lysosomal originated exosomes. The distribution of the newly sunthesiszed IL-1ß between these compartments where agonist dependant. Direct visuvalisation of unpermeabilized microparticles with Total Internal Reflection Microscopy and flowcytometry showed IL-1ß surface display. Both microparticles and exosomes contain IL-1R1 and is essential for the IL-1ß display on the particle surface. Blocking IL-1R1 in human platelets with IL-1Ra reduced IL-1ß display on the microparticle surface and complete loss of IL-1R1 in IL-1R1-/- platelet shed microparticles showed no surface IL-1ß. The shed microvesicles contain biologically active IL-1 that activates Nf-¿B driven E-selectin expression in endothelial cells in an IL-1R1 dependent fashion. Efficient IL-1 secretion is bi-parte signaling event, involving the surface receptor ligand stimulation that is closely followed by activation of ATP - induced purinergic P2X7 receptor and NLRP3 inflammasome which facilitate Caspase-1 dependent IL-1ß activation and secretion. Platelets express P2X7 receptors and Pannxein-1 channels, process IL-1ß via NLRP-3 inflammasome complex formation. Inhibition of caspase-1 activity with cell permeable peptide inhibitors, or indirect inhibition of inflammasome assembly through inhibition of P2X7 receptor and Panx-1 activation resulted in decreased IL-1ß laden microparticle release. In summary, this study has identified novel functional platelet receptors and protein complexes and the signaling pathways involved in platelet IL-1 response. This extends our understanding of the role of platelets in both septic and sterile inflammatory responses.
Thomas McIntyre, PhD. (Advisor)
Barsanjit Mazumder, PhD. (Committee Member)
Keith McCrea, MD, PhD. (Committee Member)
William Baldwin, MD, PhD. (Committee Member)
Crystal Weyman, PhD. (Other)
Carol De La Motte, PhD. (Other)
166 p.

Recommended Citations

Citations

  • Narayanan, P. (2014). Interleukin 1 Receptor1 signaling in Platelet Inflammatory responses Interleukin-1ß processing and secretion [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1425911007

    APA Style (7th edition)

  • Narayanan, Padmini. Interleukin 1 Receptor1 signaling in Platelet Inflammatory responses Interleukin-1ß processing and secretion. 2014. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1425911007.

    MLA Style (8th edition)

  • Narayanan, Padmini. "Interleukin 1 Receptor1 signaling in Platelet Inflammatory responses Interleukin-1ß processing and secretion." Doctoral dissertation, Cleveland State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1425911007

    Chicago Manual of Style (17th edition)