Abstract
A growing body of evidence implicates endoplasmic reticulum (ER) stress in the pathogenesis of chronic inflammatory and autoimmune disorders. Here, we demonstrate that the proinflammatory cytokine TNFα stimulates matrix metalloproteinase 9 (MMP9) at the ocular surface through a c-Fos-dependent mechanism of ER stress. We found positive reactivity of the molecular chaperone BiP/GRP78 in conjunctival epithelium of patients with ocular cicatricial pemphigoid and increased levels of BiP/GRP78, sXBP1 and GRP94 in human corneal epithelial cells treated with TNFα. Pharmacological blockade of ER stress in vitro using dexamethasone or the chemical chaperones TUDCA and 4PBA attenuated MMP9 expression and secretion in the presence of TNFα. Moreover, expression analysis of genes associated with inflammation and autoimmunity identified the c-Fos proto-oncogene as a mediator of ER stress responses in epithelial cells. Substantially less TNFα-induced MMP9 expression occurred when c-Fos signaling was suppressed with a function-blocking antibody. Taken together, these results indicate that activation of ER stress contributes to promote inflammation-mediated proteolytic activity and uncovers a target for restoring tissue homeostasis in ocular autoimmune disease.
Highlights
A growing body of evidence implicates endoplasmic reticulum (ER) stress in the pathogenesis of chronic inflammatory and autoimmune disorders
Incubation with tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4PBA) following TNFα stimulation significantly reduced the induction of matrix metalloproteinase 9 (MMP9) expression as well as its secretion into the cell culture media (Fig. 4b,c). These results indicate that induction of proteolytic activity in epithelial cells by the proinflammatory cytokine TNFα can be mediated by activation of ER stress
Biochemical and functional studies have implicated abnormal proteolytic activity in the pathogenesis of autoimmune disease. These analyses indicate that active matrix metalloproteinases (MMPs) cleave a diverse range of substrates such as cell surface molecules, adhesion proteins and components of the extracellular matrix to influence signaling and tissue remodeling processes[24]
Summary
A growing body of evidence implicates endoplasmic reticulum (ER) stress in the pathogenesis of chronic inflammatory and autoimmune disorders. Less TNFα-induced MMP9 expression occurred when c-Fos signaling was suppressed with a function-blocking antibody Taken together, these results indicate that activation of ER stress contributes to promote inflammation-mediated proteolytic activity and uncovers a target for restoring tissue homeostasis in ocular autoimmune disease. Disruption of ER homeostasis and accumulation of unfolded proteins can overload the ER and induce activation of specific stress signaling pathways, collectively known as the unfolded protein response (UPR)[10] It involves activation of transcription factors such as XBP1 that direct the expression of chaperones, folding enzymes and components of the ERAD pathway to relieve ER stress and restore homeostasis[11,12]. We provide evidence indicating that ER stress plays a role in promoting inflammation-mediated proteolytic activity in ocular autoimmune disease and identify the c-Fos proto-oncogene as a key mediator of these events
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