Potential regulatory molecules in the human trabecular meshwork of patients with glaucoma: Immunohistochemical profile of a number of inflammatory cytokines

Abstract

Glaucoma occurs when there are imbalances between the production and the drainage of the eye liquid. The vast majority of the aqueous humor leaves the eye through the trabecular meshwork (TM). The cause of hypertonicity may be due to an alteration in the thickness of the TM. In the majority of cases the molecular changes that determine primary open‑angle glaucoma (POAG) are unclear. However, it has been hypothesized that the significant increase in the extracellular matrix (ECM) of the fibrillary bands in the TM is associated with possible inflammatory conditions. In this study the tissue distribution of interleukin (IL)‑6, IL‑1β, transforming growth factor-β1 (TGF‑β1), vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNF‑α) was analyzed in TM samples from patients with POAG by immunohistochemistry. Seven specimens from patients with POAG and three control tissues were analyzed by immunohistochemistry using specific antibodies against these cytokines. Morphological changes in the TM, such as increased cell content, macrophages, fibrosis and accumulation of neutrophils, were observed by transmission electron microscopy. In human TM tissues, an evident immunoreactivity for IL‑6, IL‑1β and TNF‑α was observed in patients with POAG when compared with the control subjects, indicating that these cytokines may be correlated with disease activity. TM endothelial cells secrete a number of factors and cytokines that modulate the functions of the cells and the ECM of the conventional outflow pathway. In the TM in glaucoma, macrophages produce cytokines, including IL‑6, IL‑1β and TNF‑α, leading to an acute inflammatory response and recruitment of other immune cells, including T lymphocytes. In addition, TGF‑β1 regulates and induces the expression of IL‑6 in TM that indirectly induces angiogenesis by stimulating VEGF expression. The present results support previous evidence that suggests that growth factors and cytokines can induce ECM remodelling and alter cytoskeletal interactions in the TM.

Neuroinflammation in glaucoma: A new opportunity

“…In the case of uveitis, a form of glaucoma called inflammatory, or uveitic, glaucoma can result from obstruction of drainage structures in the anterior segment as a secondary consequence of the ocular inflammation (Bodh et al , 2011; Siddique et al , 2013; Baneke et al , 2015). In the case of steroid-induced glaucoma, the steroids are generally thought to be deleterious, not by their action in reducing inflammation, but rather by acting directly to affect the drainage structures, among other things, by increasing extracellular matrix deposition by trabecular meshwork cells, which increases outflow resistance and consequently increased intraocular pressure (Clark et al , 1995; Tektas et al , 2011; Overby et al , 2014; Raghunathan et al , 2015; Taurone et al , 2015). This paradoxical relationship between inflammation and glaucoma (both inflammation and anti-inflammatory treatment can give you glaucoma), together with the absence of obvious large-scale lymphocyte infiltration into the retina (Yang et al , 2001; Tezel and Wax, 2004), have contributed to the generally held notion among clinicians that human glaucoma is not an inflammatory disease.…”

“…In addition, intrinsic up-regulation of complement molecules in RGCs (such as C1qa and C3) occurs early and mediates synaptic dysfunction. From Soto and Howell 2015 (Soto and Howell, 2014). …”

The Outflow Pathway: A Tissue With Morphological and Functional Unity

“…During glaucoma, macrophages in the TM produce cytokines, including IL‐6, IL‐1β, and TNF‐α, leading to an acute inflammatory response. These cytokines may induce ECM remodeling and alter cytoskeletal interactions in the TM (Taurone et al, ). IL‐6 has been seen to increase outflow facility in perfused anterior segments of porcine eyes (Liton et al, ), and IL‐8 modulates the permeability of the endothelial cells of SC (Alvarado et al, ).…”

Growth Differentiation Factor-15–Induced Contractile Activity and Extracellular Matrix Production in Human Trabecular Meshwork Cells

“…While it now is widely recognized that the autocrine and paracrine actions of factors secreted by the TM and SC cells influence their cellular characteristics with subsequent impact on AH outflow and IOP, 30,44–46 we lack comprehensive understanding of the identity of such factors. In this study, we showed that human TM cells express and secrete GDF-15.…”