July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
TNFα induces corneal epithelial proteolytic activity in response to ER stress
Author Affiliations & Notes
  • Ashley Woodward
    Schepens Eye Research Institute/MEE/HMS, Boston, Massachusetts, United States
  • Antonio Di zazzo
    University Campus Bio-Medico, Rome, Italy
  • Stefano Bonini
    University Campus Bio-Medico, Rome, Italy
  • Pablo Argueso
    Schepens Eye Research Institute/MEE/HMS, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Ashley Woodward, None; Antonio Di zazzo, None; Stefano Bonini, None; Pablo Argueso, None
  • Footnotes
    Support  NIH Grant EY026147
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 912. doi:
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    • Get Citation

      Ashley Woodward, Antonio Di zazzo, Stefano Bonini, Pablo Argueso; TNFα induces corneal epithelial proteolytic activity in response to ER stress. Invest. Ophthalmol. Vis. Sci. 2019;60(9):912.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : There is a growing body of evidence implicating endoplasmic reticulum (ER) stress in the pathogenesis of chronic inflammatory and autoimmune disorders. Here, we investigated whether ER stress mediates TNFα-induced matrix metalloproteinase-9 (MMP9) activity in human corneal epithelial cells.

Methods : Tissue sections and impression cytology samples were collected from patients with ocular pemphigoid and healthy control subjects. Protein and mRNA were isolated from stratified cultures of human corneal epithelial cells. Human samples and cell culture isolates were subjected to immunohistochemical staining, immunoblot, gel zymography, and qRT-PCR for ER stress markers (BiP/sXBP1/GRP94) and MMP9. To inhibit ER stress, cultures were treated with the pharmacological agent dexamethasone or the chemical chaperones 4PBA and TUDCA. The effect of ER stress and TNFα on the expression of immune signaling molecules was analyzed using a human cytokine/chemokine PCR array and qRT-PCR.

Results : Conjunctival epithelial cells of patients with ocular pemphigoid and corneal epithelial cell cultures treated with TNFα displayed elevated levels of ER stress sensors and MMP9. Alleviation of TNFα-induced ER stress in vitro attenuated MMP9 expression and activity. Moreover, profiling of gene expression by PCR array identified the proto-oncogene FOS as a major mediator of ER stress in corneal epithelial cells. Substantially less MMP9 expression occurred in TNFα treated cells when FOS signaling was inhibited using a function-blocking antibody.

Conclusions : Taken together, these data indicate that activation of ER stress plays a crucial role in promoting proteolytic activity at the ocular surface and uncovers a novel therapeutic target for restoring tissue homeostasis in ocular inflammatory disease.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.


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