title: Mitochondria mediates caspase-dependent and independent retinal cell death in Staphylococcus aureus endophthalmitis.
abstract: Bacterial endophthalmitis, a vision-threatening complication of ocular surgery or trauma, is characterized by increased intraocular inflammation and retinal tissue damage. Although significant vision loss in endophthalmitis has been linked to retinal cell death, the underlying mechanisms of cell death remain elusive. In this study, using a mouse model of Staphylococcus aureus endophthalmitis and cultured human retinal Müller glia (MIO-M1 cell line), we demonstrate that S. aureus caused significant apoptotic cell death in the mouse retina and Müller glia, as evidenced by increased number of terminal dUTP nick end labeling and Annexin V and propidium iodide-positive cells. Immunohistochemistry and western blot studies revealed the reduction in mitochondrial membrane potential (JC-1 staining), release of cytochrome c into the cytosol, translocation of Bax to the mitochondria and the activation of caspase-9 and -3 in S. aureus-infected retina/retinal cells. In addition, the activation of PARP-1 and the release of apoptosis inducing factor from mitochondria was also observed in S. aureus-infected retinal cells. Inhibition studies using pan-caspase (Q-VD-OPH) and PARP-1 (DPQ) inhibitors showed significant reduction in S. aureus-induced retinal cell death both in vivo and in vitro. Together, our findings demonstrate that in bacterial endophthalmitis, retinal cells undergo apoptosis in the both caspase-dependent and independent manners, and mitochondria have a central role in this process. Hence, targeting the identified signaling pathways may provide the rationale to design therapeutic interventions to prevent bystander retinal tissue damage in bacterial endophthalmitis.
authors.affiliation: Kresge Eye Institute/Department of Ophthalmology, Wayne State University, Detroit, MI, USA; Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Kresge Eye Institute/Department of Ophthalmology, Wayne State University, Detroit, MI, USA; Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI, USA; Department of Immunology and Microbiology, Wayne State University, Detroit, MI, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kumar