NRF2/ARE mediated antioxidant response to glaucoma: role of glia and retinal ganglion cells

Abstract Glaucoma, the second leading cause of irreversible blindness worldwide, is associated with age and sensitivity to intraocular pressure (IOP). We have shown that elevated IOP causes an early increase in levels of reactive oxygen species (ROS) in the microbead occlusion mouse model. We also detected an endogenous antioxidant response mediated by Nuclear factor erythroid 2-Related Factor 2 (NRF2), a transcription factor that binds to the antioxidant response element (ARE) and increases transcription of antioxidant genes. Our previous studies show that inhibiting this pathway results in earlier and greater glaucoma pathology. In this study, we sought to determine if this endogenous antioxidant response is driven by the retinal ganglion cells (RGCs) or glial cells. We used Nrf2fl/fl mice and cell-type specific adeno-associated viruses (AAVs) expressing Cre to alter Nrf2 levels in either the RGCs or glial cells. Then, we quantified the endogenous antioxidant response, visual function and optic nerve histology after IOP elevation. We found that knock-down of Nrf2 in either cell type blunts the antioxidant response and results in earlier pathology and vision loss. Further, we show that delivery of Nrf2 to the RGCs is sufficient to provide neuroprotection. In summary, both the RGCs and glial cells contribute to the antioxidant response, but treatment of the RGCs alone with increased Nrf2 is sufficient to delay onset of vision loss and axon degeneration in this induced model of glaucoma

Immune Mediators of protective and pathogenic immune responses in patients with mild and fatal human monocytotropic ehrlichiosis

<p>Abstract</p> <p>Background</p> <p><it>Ehrlichia chaffeens</it>is is a bacterial pathogen that causes fatal human monocytic ehrlichiosis (HME) that mimic toxic shock-like syndrome. Murine studies indicate that over activation of cellular immunity followed by immune suppression plays a central role in mediating tissue injury and organ failure during fatal HME. However, there are no human studies that examine the correlates of resistance or susceptibility to severe and fatal HME.</p> <p>Results</p> <p>In this study, we compared the immune responses in two patients with mild/non fatal and severe/fatal HME who had marked lymphopenia, thrombocytopenia and elevated liver enzymes. The levels of different immunological factors in the blood of those patients were examined and compared to healthy controls. Our data showed that fatal HME is associated with defective production of Th1 cytokines such as ( IFNγ and IL-2), increased anti-inflammatory (IL-10 and IL-13) and pro-inflammatory (TNF-α, IL-1α, IL-1β, and IL-6) cytokines, increased levels of macrophages, T cells, and NK cells chemokines such as MCP-1, MIP-1α, MIP-1β, but not RANTES and IP-10, increased levels of neutrophils chemokine and growth factor (IL-8 and G-CSF), and elevated expression of tumor necrosis factor receptor (TNFR), and toll like receptors 2 and 4 compared to patients with non fatal HME and healthy controls.</p> <p>Conclusions</p> <p>Fatal <it>Ehrlichia</it>-induced toxic shock is associated with defective Th1 responses, possible immune suppression mediated by IL-10. In addition, marked leukopenia observed in patients with fatal disease could be attributed to enhanced apoptosis of leukocytes and/or elevated chemokine production that could promote migration of immune cells to sites of infection causing tissue injury.</p