Activation of HIF-1α (hypoxia inducible factor-1α) prevents dry eye-induced acinar cell death in the lacrimal gland

Abstract

The pathogenesis of immune-mediated lacrimal gland (LG) dysfunction in Sjögren's syndrome has been thoroughly studied. However, the majority of dry eye (DE) is not related to Sjögren type, and its pathophysiology remains unclear. The purpose of this study was to determine and investigate the protective mechanisms against DE stress in mice. DE induced prominent blood vessel loss without apoptosis or necrosis in the LG. Autophagic vacuoles, distressed mitochondria, and stressed endoplasmic reticulum were observed via electron microscopy. Immunoblotting confirmed the increase in autophagic markers. Glycolytic activities were enhanced with increasing levels of succinate and malate that, in turn, activated hypoxia-inducible factor (HIF)-1α. Interestingly, the areas of stable HIF-1α expression overlapped with COX-2 and MMP-9 upregulation in LGs of DE-induced mice. We generated HIF-1α conditional knockout (CKO) mice in which HIF-1α expression was lost in the LG. Surprisingly, normal LG polarities and morphologies were completely lost with DE induction, and tremendous acinar cell apoptosis was observed. Similar to Sjögren's syndrome, CD3+ and CD11b+ cells infiltrated HIF-1α CKO LGs. Our results show that DE induced the expression of HIF-1α that activated autophagy signals to prevent further acinar cell damage and to maintain normal LG function.

Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway

“…High expression of HIF-1α may promote RA in synovial tissues, secrete chemotactic factors, recruit monocytes, T and B lymphocytes, reinforce differentiation of T helper 17 cells directly and participate in the overall inflammatory response of RA (31). Furthermore, HIF-1α may additionally promote VEGF expression and the subsequent generation of blood vessels (31). In the present study, gambogic acid significantly suppressed the activation of HIF-1α protein expression in RA rats.…”

“…The RA intra-articular environment is an anaerobic environment which leads to high expression of HIF-1α in synovial tissues (30). High expression of HIF-1α may promote RA in synovial tissues, secrete chemotactic factors, recruit monocytes, T and B lymphocytes, reinforce differentiation of T helper 17 cells directly and participate in the overall inflammatory response of RA (31). Furthermore, HIF-1α may additionally promote VEGF expression and the subsequent generation of blood vessels (31).…”

Rapamycin Rescues Endoplasmic Reticulum Stress–Induced Dry Eye Syndrome in Mice

“…24 Oxidative stress and ER stress also contribute to the pathophysiology of dry eye syndrome. 5,6,25,26 In this study, tunicamycin, an ER stress inducer, 27 reduced tear production, increased blinking rate, and increased corneal FSS, which are all hallmarks of dry eye syndrome. 28,29 This study is the first to report dry eye syndrome by inducing ER stress in mice by injection of tunicamycin, different from the previous studies using NOD mice.…”

“…PECAM-1 is a molecule expressed on all cells within the vascular compartment. 5 PECAM-1 was investigated as a vascular marker because it is expressed in endothelial cells 5 although it is also expressed in platelets and leukocytes. 43 VE-cadherin was evaluated as a specific vascular endothelial cell marker.…”

“…4 Recently, endoplasmic reticulum (ER) stress has been suggested as a pathophysiology of dry eye syndrome. 5,6 ER stress has been described in many diseases, including cardiovascular disorders, neurodegenerative diseases, inflammatory bowel disease, and rheumatoid arthritis. 7,8 The ER is a cellular organelle in which proteins and lipids are synthesized and processed, and metabolism of xenobiotic compounds occurs.…”