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Shuang Zhu, Hua Liu, Yonju Ha, Dianshuai Gao, Wenbo Zhang; PERK and XBP1s differentially regulate CXCL10 and CCL2 production in photoreceptor cells. Invest. Ophthalmol. Vis. Sci. 2016;57(12):559.
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© ARVO (1962-2015); The Authors (2016-present)
Inflammation plays a key role in the pathogenesis of many retinal degenerative diseases related with photoreceptor dysfunction/degeneration. However the involvement of photoreceptor cells in inflammatory reactions is largely unknown as they are not considered as inflammatory cells. CCL2 and CXCL10 are two chemokines to recruit monocytes, microglia and T cells to the sites of inflammation.It has been reported that endoplasmic reticulum (ER) stress, which contains three pathways: PERK, ATF6 and IRE1, is also involved in the inflammatory response.In this study, we assessed whether photoreceptor cells can produce CCL2 and CXCL10 during ER stress.
Photoreceptor cell line 661W is a generous gift from Dr. Muayyad Al-Ubaidi. Cells were treated with thapsigargin (TG, 0.01 μM), an ER stress inducer, and levels of CXCL10, CCL2, ER stress markers, p-NF-kB p65, NF-kB p65, p-STAT3, and STAT3 were measured by qPCR, ELISA, and/or Western blot. ER stress pathways PERK and XBP1s,NF-kB p65 and STAT3 pathways were blocked by shRNAs or inhibitors.
Induction of ER stress with TG in photoreceptor cells induced CXCL10 and CCL2 expression at both mRNA and protein levels.TG-induced CXCL10 and CCL2 expression was significantly blocked by phenylbutyric acid, a blocker of ER stress. Knockdown of PERK attenuated TG-induced CXCL10 and CCL2 mRNA expression by 30.1% and 59.5%, respectively, associated with significant decreases in phosphorylation of NF-kB p65 and STAT3. Blockade of NF-kB with PTDC or STAT3 with Stattic markedly attenuated TG-induced CXCL10 and CCL2 expression. In contrast to PERK, knockdown of XBP1s, which is formed by activated IRE1α-mediated splicing and serves as a major protective molecule in the unfolded protein response (UPR) when cells are under ER stress, robustly enhanced TG-induced CXCL10 and CCL2 expression and phosphorylation of NF-kB p65 and STAT3.
These studies suggest that photoreceptors may be involved in retinal inflammatory reactions during diseases by expressing chemokines CXCL10 and CCL2. PERK and IRE1/XBP1s in the UPR differentially regulate the expression of CXCL10 and CCL2 likely through modulation of ER stress-induced NF-kB p65 and STAT3 activation.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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