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Melinda K Duncan, jian jiang, Mahbubul Shihan, Yan Wang, Samuel Novo; Lens epithelial cells rapidly initiate the innate immune response following cataract surgery. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1607.
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© ARVO (1962-2015); The Authors (2016-present)
Surgery is an effective treatment for cataract, however, both post-surgical ocular inflammation and posterior capsular opacification (PCO) inhibit post-surgical recovery and long term visual acuity post cataract surgery (PCS). While transforming growth factor beta (TGFβ) is a major player in PCO pathogenesis, little is known about what initiates this process. Here we seek to understand how lens epithelial cells (LECs) responses to cataract surgery that occur PRIOR to TGFβ pathway activation may contribute to cataract surgery side-effects.
Lens fiber cells were removed from adult wild type (WT) mice to model cataract surgery. RNA was isolated from the remnant LECs either immediately following surgery (0 hr. PCS) or 24 hours later (24 hr PCS) (three biological replicates, 5 PCS lenses per replicate). RNA-Seq libraries were produced from this RNA and sequenced on an Illumina HiSeq 2000. Significant changes in gene expression and their time course were validated by immunolocalization of capsular bags.
RNA-seq revealed that the LEC transcriptome is drastically altered by 24 hours PCS, which is a day before the onset of detectable canonical TGFβ signaling. Notably, over 1/3 of the 200 most upregulated genes are involved in the innate immune response. The three most upregulated genes at 24 hours PCS are CXCL1 (3800 fold), S100A9 (1500 fold) and Colony stimulating factor 3 (1100 fold), all mediators of innate immunity. Immunolocalization revealed that all of these genes have upregulated in LECs by 6 hrs PCS, show a peak around 24 hours PCS and sharply downregulate by 3 days PCS. Since these factors help leukocytes home to injury sites, we immunostained capsular bags for ITGAM (integrin alphaM/CD11b, a marker of leukocytes) whose mRNA levels were upregulated 9 fold in lens capsular bags at 24 hrs PCS. This analysis revealed that leukocytes first associate with lens capsular bags at 18 hrs PCS, increase between 24 and 48 hours PCS, and are largely gone by 10 days PCS.
As ocular inflammation is seen at 24 hrs PCS in humans, and LECs upregulate pro-inflammatory cytokines by 6 hrs PCS, this suggests that LECs, at least in part, drive ocular inflammation PCS. As inflammation can activate latent TGFβ, this may initiate PCO pathogenesis.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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