Lens Epithelial Cells Initiate an Inflammatory Response Following Cataract Surgery

Abstract

PurposeLens epithelial cell (LEC) conversion to myofibroblast is responsible for fibrotic cataract surgery complications including posterior capsular opacification. While transforming growth factor beta (TGFβ) signaling is important, the mechanisms by which the TGFβ pathway is activated post cataract surgery (PCS) are not well understood.MethodsRNA-seq was performed on LECs obtained from a mouse cataract surgery model at the time of surgery and 24 hours later. Bioinformatic analysis was performed with iPathwayGuide. Expression dynamics were determined by immunofluorescence.ResultsThe LEC transcriptome is massively altered by 24 hours PCS. The differentially expressed genes included those important for lens biology, and fibrotic markers. However, the most dramatic changes were in the expression of genes regulating the innate immune response, with the top three altered genes exhibiting greater than 1000-fold upregulation. Immunolocalization revealed that CXCL1, S100a9, CSF3, COX-2, CCL2, LCN2, and HMOX1 protein levels upregulate in LECs between 1 hour and 6 hours PCS and peak at 24 hours PCS, while their levels sharply attenuate by 3 days PCS. This massive upregulation of known inflammatory mediators precedes the infiltration of neutrophils into the eye at 18 hours PCS, the upregulation of canonical TGFβ signaling at 48 hours PCS, and the infiltration of macrophages at 3 days PCS.ConclusionsThese data demonstrate that LECs produce proinflammatory cytokines immediately following lens injury that could drive postsurgical flare, and suggest that inflammation may be a major player in the onset of lens-associated fibrotic disease PCS.

The effects of c-Src kinase on EMT signaling pathway in human lens epithelial cells associated with lens diseases

“…ASC and PCO share many molecular features such as aberrant proliferation, migration and epithelial to mesenchymal transition (EMT) of lens epithelial cells (LECs) [5]. Accumulating evidence shows that antiinflammation treatments after cataract surgery could reduce migration and fibrosis of LECs [6][7][8]. It has been reported that fibrosis of LECs in patients with diabetes mellitus was significantly higher than in patients without diabetes at 6 and 12 months after cataract extraction [9].…”

TPM3.1 association with actin stress fibers is required for lens epithelial to mesenchymal transition

“…Next, we induced EMT by exposing imLECs to TGFβ2. We chose to treat cells with TGFβ2 as it has been shown to be present in the aqueous humor 18 , it is increased in the aqueous humor following lens injury and inflammation 19, 20 , and it has been shown to be more potent than TGFβ1 in enhancing EMT 21 . Exposure of imLECs to 5ng/mL TGFβ2 downregulated Tpm 1.9 and Tpm1.13 mRNA levels, upregulated Tpm1.7, 2.1, 3.1, and 4.2 mRNA levels, but did not affect Tpm1.5 and Tpm3.5 mRNA levels (Figure 1A and 1B).…”

“…Inhibition of stress fiber-associated Tpms, such as Tpm3.1, may be a means to repress stress fiber formation and EMT during TGFβ2 stimulation of lens epithelial cells. Further studies aimed at elucidating Tpm3.1 in in vitro human cataract model systems 34 as well as in vivo cataract animal models 19 are required to determine the therapeutic potential of targeting Tpm3.1 in cataracts. Targeting Tpms could be a promising route to prevent EMT and cataractogenesis.…”

The role of lipocalin-2 in age-related macular degeneration (AMD)

“…Stabilization of MMP-9 by LCN-2 could also facilitate VEGF liberation thus promoting angiogenesis [99]. Interestingly, the interaction between LCN-2 and MMP-9 could also contribute to the TGF β-mediated epithelial-tomesenchymal transition of the lens epithelial cells following cataract surgery [100,101].…”