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Tytteli Turunen, Marie Shatos, Gianna C Teague, Fatima Absar, Kameran Lashkari; Systemic and Local Sources of Interferon-gamma Inducible Chemokines in The Pathogenesis of AMD. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2328.
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Inflammation plays an important role in pathogenesis of AMD. Identifying pro-inflammatory factors that participate in inflammatory signaling may elucidate the underlying pathogenesis of AMD and help identify novel therapeutic targets for treatment. We have previously identified interferon inducible factor-10 (IP-10/CXC10) as one of the pro-inflammatory chemokines in AMD. In this study we have investigated the systemic sources of IP-10 and its sister molecules, MIG (CXCL9) and ITAC (CXCL11) in circulating leukocytes and postmortem spleen specimens matched to ocular tissue and staged for AMD.
Subjects with AMD were clinically classified according to AREDS; early and intermediate dry AMD (AREDS I and AREDS III), geographic atrophy, active and inactive neovascular AMD, and age-matched control. Buffy coats were derived from whole blood samples and subjected to flow cytometry analysis (FACS) for expression of MIG, IP-10, ITAC and CXCR3 in the various circulating leukocytes. Matched postmortem eye and spleen specimens were staged for AMD and subjected to immunohistochemistry for expression of these chemokines.
FACS analysis showed that circulating CD14+ monocytes expressed increased levels of IP-10 and MIG in all AMD phenotypes as compared to age-matched controls (Wilcoxon test, p<0.05). ITAC expression was not affected by the stage of AMD (p=0.31). IHC of spleens matched to ocular specimens of AMD donors showed increased expression of IP-10 and MIG in spleen cells in the white pulp around marginal zones in early AMD. These factors were identified in RPE and drusen deposits and correlated with stage of AMD. Interestingly, CXCR3 expression was not affected.
Our data indicates that IP-10 and MIG are closely associated with stage of AMD through both local and systemic sources. CD14+ monocytes are a primary source of systemic chemokine support in AMD and may contribute to maintaining a pro-inflammatory state. These chemokines and their receptors may be novel therapeutic targets for anti-inflammatory treatment of AMD.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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