EMMPRIN Modulates Epithelial Barrier Function through a MMP–Mediated Occludin Cleavage

Abstract

Dry eye is a common disease that develops as a result of alteration of tear fluid, leading to osmotic stress and a perturbed epithelial barrier. Matrix metalloproteinase-9 (MMP-9) may be important in dry eye disease, as its genetic knockout conferred resistance to the epithelial disruption. We show that extracellular matrix metalloproteinase inducer (EMMPRIN; also termed CD147), an inducer of MMP expression, participates in the pathogenesis of dry eye through MMPmediated cleavage of occludin, an important component of tight junctions. EMMPRIN expression was increased on the ocular surface of dry eye patients and correlated with those of MMP-9. High osmolarity in cell culture, mimicking dry eye conditions, increased both EMMPRIN and MMP-9 and resulted in the disruption of epithelial junctions through the cleavage of occludin. Exogenously added recombinant EMMPRIN had similar effects that were abrogated in the presence of the MMP inhibitor marimastat. Membrane occludin immunostaining was markedly increased in the apical corneal epithelium of both EMMPRIN and MMP-9 knock-out mice. Furthermore, an inverse correlation between EMMPRIN and occludin membrane staining was consistently observed both in vitro and in vivo as a function of corneal epithelial cells differentiation. These data suggest a possible role of EMMPRIN in regulating the amount of occludin at the cell surface in homeostasis beyond pathological situations such as dry eye disease, and EMMPRIN may be essential for the formation and maintenance of organized epithelial structure. (Am J Pathol

Molecular basis for MMP9 induction and disruption of epithelial cell-cell contacts by galectin-3

“…MMP9 is the primary metalloproteinase synthesized and secreted by basal cells at the leading edge of migrating epithelium (Sivak et al, 2004). Moreover, MMP9 has been associated with the cleavage of occludin through a CD147-dependent mechanism (Huet et al, 2011). In our experiments, addition of rGal-3 to keratinocytes resulted in increased secretion of MMP9 in a dose-and lactosedependent manner, concomitant with upregulation of MMP9 mRNA levels (Fig.…”

Dry Eye Profiles in Patients with a Positive Elevated Surface Matrix Metalloproteinase 9 Point-of-Care Test Versus Negative Patients

“…In contrast, an inflammatory response was noted in the setting of higher osmolarity concentrations (400 to 600 mOsm/L). 39 The presence of corneal somatosensory dysfunction may lead to DE symptoms that are dissociated from peripheral ocular surface pathology. Many patients with DE symptoms report features of neuropathic ocular pain, including spontaneous pain, dysesthesias, hyperalgesia, and allodynia.…”

The role and treatment of inflammation in dry eye disease

“…As the process continues, the objective is to develop agents which contain tear contents and stimulate natural tears and new and more effective immunomodulators other than CsA. Some intensive studies of the subject address the completion of basic mediators in tears which exist in healthy tears and maintain ocular surface homeostasis, and the specific blockage of inflammatory mediators which have a key role in dry eye [101]. …”

“…TNF-a blockers which suppress the inflammation in the lacrimal gland and cornea may be effective treatment options in dry eye treatment [100,101].…”