Subtypes of Macrophages and Interaction of Macrophages with the RPE. In collaboration with Dr. Siamon Gordon in Oxford and Dr. Miller at the NEI, we have initiated studies on human macrophages focusing on 1) the interaction of human macrophages with human retinal pigmented epithelial cells and 2) phenotypic and functional heterogeneity of human macrophages and its implication in autoimmune intraocular inflammatory diseases. We have found that human RPE cells can interfere with the normal processes of differentiation and maturation of macrophages. We then evaluated monocytes'role in the development of intermediate, posterior and panuveitis. Preliminary data showed that immuno-suppression enrich anti-proinfllammatory monocytes in patients'peripheral blood, implying that regulatory monocytes can serve as a prognosis marker for uveitis. We further showed that different types of monocytes interact T cells in different modes. Immune factors leading to CNV By adapting and modifying a commonly used laser induced CNV mouse model, we have established a strategy to investigate the involvement and potential mechanisms of immune responses in CNV, the most common complication in AMD and other important eye diseases. We have combined flow cytometry, vibrotome immunohistochemistry and flat-mount techniques plus confocal immunomicroscopy to evaluate the model. We have discovered that there is a dynamic and complex movement of immune cells during the development ofCNV in the mouse. Macrophages have been implicated in the pathogenesis of AMD. Class A scavenger receptors, SR-A and MARCO, are expressed on macrophages and are associated with macrophage function. The goal of this study is to examine the role of macrophage scavenger receptors in immune cell recruitment and the formation of CNV. Laser photocoagulation was performed in Wild Type and knockout mice with deletion of SR-A (SR-A-/-), MARCO (MARCO-/-), or both SR-A and MARCO (DKO). Immune cell recruitment at different time points and CNV lesions at 14 days after laser treatment were evaluated through immunostaining and confocal microscopy. Microarray analysis was performed in eyes 1 day after laser injury. Wild Type eyes showed higher chemokine/receptor expression compared with knockout eyes after laser injury. Scavenger receptor deficiency markedly impaired the recruitment of neutrophils and macrophages to CNV lesions at 1 day and 3 days post laser injury, respectively. Significantly reduced CNV volumes were found in the eyes from scavenger receptor knockout mice compared with Wild Type mice. The deficiency of scavenger receptors impairs the formation of CNV and immune cell recruitment. Our findings suggest a potential role for scavenger receptors in contributing to CNV formation and inflammation in AMD. Complement and the immune response. Several reports have associated SNPs of complement factor H with either susceptibility to or protection against AMD. This association has been attributed to involvement of the innate immune system, presumably through macrophage activity and Toll-like receptors. We have looked at this question differently;rather that complement and its components may be part of the acquired immune system. We have showed that C5a promoted IL-22 and IL-17 expression from human CD4+ T cells of AMD patients and normals accompanied by the expression of the transcription factor BATF. This effect was dependent on B7, IL-1beta and IL-6 expression from monocytes. Intriguingly, we found significantly increased levels of IL-22 in the serum of 22 AMD patients and the vitreous of one AMD patient as compared to non-AMD controls, strongly suggesting possible roles of IL-22 and IL-17 in the inflammation that contributes to AMD. We also showed that IL-22 directly decreased retinal pigment epithelium (RPE) viability. RPE loss is a consistent feature of the development of advanced AMD. In addition to the role of C5a in T cell differentiation, C5a also decreases human RPE cell viability and abrogates the suppressive effect of RPE on T cells. Thus, our data suggest an underlying mechanism of chronic inflammation leading to retinal degeneration which may herald a new approach to treat AMD.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000464-06
Application #
8737644
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$113,468
Indirect Cost
Name
U.S. National Eye Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Knickelbein, Jared E; Liu, Baoying; Arakelyan, Anush et al. (2016) Modulation of Immune Responses by Extracellular Vesicles From Retinal Pigment Epithelium. Invest Ophthalmol Vis Sci 57:4101-7
Chen, Ping; Urzua, Cristhian A; Knickelbein, Jared E et al. (2016) Elevated CD1c+ Myeloid Dendritic Cell Proportions Associate With Clinical Activity and Predict Disease Reactivation in Noninfectious Uveitis. Invest Ophthalmol Vis Sci 57:1765-72
Liu, Baoying; Dhanda, Ashwin; Hirani, Sima et al. (2015) CD14++CD16+ Monocytes Are Enriched by Glucocorticoid Treatment and Are Functionally Attenuated in Driving Effector T Cell Responses. J Immunol 194:5150-60
Schewitz-Bowers, Lauren P; Lait, Philippa J P; Copland, David A et al. (2015) Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A. Proc Natl Acad Sci U S A 112:4080-5
Chen, Ping; Denniston, Alastair; Hannes, Susan et al. (2015) Increased CD1c+ mDC1 with mature phenotype regulated by TNFα-p38 MAPK in autoimmune ocular inflammatory disease. Clin Immunol 158:35-46
Dagur, Pradeep K; Biancotto, Angélique; Stansky, Elena et al. (2014) Secretion of interleukin-17 by CD8+ T cells expressing CD146 (MCAM). Clin Immunol 152:36-47
Nussenblatt, Robert B; Lee, Richard W J; Chew, Emily et al. (2014) Immune responses in age-related macular degeneration and a possible long-term therapeutic strategy for prevention. Am J Ophthalmol 158:5-11.e2
Lima, Breno R; Mandelcorn, Efrem D; Bakshi, Nupura et al. (2014) Syphilitic outer retinopathy. Ocul Immunol Inflamm 22:4-8
Wu, Wenting; Jin, Ming; Wang, Yujuan et al. (2014) Overexpression of IL-17RC associated with ocular sarcoidosis. J Transl Med 12:152
Jawad, Shayma; Liu, Baoying; Agron, Elvira et al. (2013) Elevated Serum Levels of Interleukin-17A in Uveitis Patients. Ocul Immunol Inflamm :

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