Autophagy in graves' ophthalmopathy

Abstract

Graves' ophthalmopathy (GO) is an inflammatory autoimmune disease that affects the eyes. It can significantly alter the quality of life in patients because of its distinctive pathological appearance and the effect on vision. To date, the exact pathological mechanism of GO has not been explicitly discovered. However, several studies have associated autophagy with this disease. Autophagy is a catabolic process that helps maintain homeostasis in all organisms by protecting the cells and tissues from various endogenous and exogenous stress factors. Based on our results, patients affected with GO have comparatively elevated levels of autophagy, which critically affects the pathological mechanism of the GO. In this review, we have summarized the autophagy mechanism in the pathogenesis of GO.

Keywords: adipogenesis; autophagy; glycosaminoglycan; graves’ ophthalmopathy; inflammation.

FIGURE 1

Major regulatory signaling pathways of autophagy. Autophagy is a process consisting of initiation, elongation, maturation and degradation steps. The PI3K-AKT pathway is the upstream activator of mTORC1, whereas AMPK initiates autophagy by inhibiting the mTORC1 activity or directly activating the ULK1/2 complex. mTORC1 activation inhibits autophagy by inhibiting the ULK1/2 complex, which is necessary for the induction of autophagy. When activating the ULK1/2 complex, it can recruit Beclin 1/III class PI3K complexes to the site of autophagosome formation. LC3-II exerts an essential role in the formation of autophagosome through binding to the autophagosomal membrane. P62 can serve as a connection between LC3 and ubiquitinated proteins. Autophagosome fuses with lysosome to form autolysosome. Eventually, autolysosome is degraded by lysosomal enzymes. We have highlighted in red the autophagic steps linked to inflammation, adipogenesis and HA accumulation in GO that have been discussed in this review. mTORC1, Rapamycin complex 1; ER, endoplasmic reticulum; rapamycin (mTOR) kinase; AMPK, AMP-dependent protein kinase; PI3K-AKT pathway, phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT) pathway; ULK1/2 complex, UNC-51–like kinase1 or 2; LC3, light chain 3 protein; ATG, autophagy related genes; CQ, Chloroquine; HCQ, hydroxychloroquine.

FIGURE 2

Autophagy regulation in GO pathogenesis. The underlying mechanisms of GO has been linked to inflammation, adipogenesis, and GAG accumulation in OFs, and finally lead to enlarged extraocular muscles with orbital fat expansion. Elevated secretion of inflammatory factors such as TNF-α, IL-1β, and INF-γ is associated with the induction of autophagy in OFs of GO. Progression of OFs adipogenesis can be mitigated by inhibition of autophagy. Furthermore, lysosomal inhibitors can reduce GAG accumulation through blocking the autophagic flux of OFs in GO. TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin-1 beta; INF-γ, interferon-gamma.