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Caspase-1-Dependent Inflammatory Signaling in Retinal Müller Cells During the Development of Diabetic Retinopathy

Trueblood, Katherine Eileen

Abstract Details

2011, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Diabetic retinopathy, a common complication of diabetes, is the leading cause of blindness in adults in the United States. It is known that high blood glucose levels result in initiation of an inflammatory response in the eye, contributing to the development of disease. This inflammatory response is characterized by elevated levels of activated of caspase-1, an inflammatory mediator protein, and increased production of the inflammatory cytokine, interleukin-1-β (IL-1β). Retinal Müller cells are one source of inflammatory signaling molecules in the retina and possibly participate in the development and progression of diabetic retinopathy. However, how high blood glucose levels regulate caspase-1 activation is incompletely understood. In this dissertation, I characterized: (1) how extracellular purines act as autocrine/paracrine mediators of high glucose-induced signaling cascades that converge on activation of caspase-1 in a cultured rat Müller cell model (rMC-1); and (2) the role of an IL-1β driven autocrine feedback mechanism in mediating acellular capillary degeneration. My findings support a novel role for autocrine P1 and P2 purinergic receptors coupled to cAMP signaling cascades and transcriptional induction of caspase-1 in mediating high glucose-induced activation of caspase-1 and secretion of IL-1β in a cell culture model of retinal Müller cells. My studies also indicate that sustained caspase-1 activation is crucial for the development of diabetic retinopathy as caspase-1 knock-out mice did not develop acellular capillaries, a hallmark of the disease. High glucose-induced a multiphasic pattern of caspase-1 activation in the retina in vivo and in rMC-1 in vitro. Blocking IL-1β mediated signaling using IL-1 receptor antagonist prevented the sustained, degenerative phase of caspase-1 activation suggestive of an IL-1β autocrine feedback mechanism in vitro. In vivo studies supported this model by demonstrating that knock-out of the interleukin-1 receptor prevented sustained activation of caspase-1 in the diabetic retina in addition to protecting against acellular capillary formation. Future experiments defining a specific role for the NLRP3 inflammasome, a multi-protein complex that regulates caspase-1 activation in hematopoietic cells during microbial infection, may provide additional insight regarding the molecular mechanisms by which high glucose induces caspase-1 activation in these non-hematopoietic Müller cells that contribute to sterile inflammation in the retina.
George Dubyak, R (Advisor)
Corey Smith (Committee Chair)
Thomas McCormick (Committee Member)
Margaret Chandler (Committee Member)
Patrick Wintrode (Committee Member)
Thomas Nosek (Committee Member)
219 p.

Recommended Citations

Citations

  • Trueblood, K. E. (2011). Caspase-1-Dependent Inflammatory Signaling in Retinal Müller Cells During the Development of Diabetic Retinopathy [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1322483450

    APA Style (7th edition)

  • Trueblood, Katherine. Caspase-1-Dependent Inflammatory Signaling in Retinal Müller Cells During the Development of Diabetic Retinopathy. 2011. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1322483450.

    MLA Style (8th edition)

  • Trueblood, Katherine. "Caspase-1-Dependent Inflammatory Signaling in Retinal Müller Cells During the Development of Diabetic Retinopathy." Doctoral dissertation, Case Western Reserve University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1322483450

    Chicago Manual of Style (17th edition)