Resolvin D1 protects against Aspergillus fumigatus keratitis in diabetes by blocking the MAPK-NF-κB pathway.

Abstract

Fungal keratitis (FK) is one of the main causes of blindness in China. People with diabetes are susceptible to corneal epithelial disease, even fungal keratitis. At present, there are few studies on this disease. Resolvins (Rv) has been reported as a mediators that exert crucial anti-inflammatory and immune regulation roles in serval diseases. In order to investigate the roles and underlying mechanism of Resolvins D1 (RvD1) on the Aspergillus fumigatus (A. fumigatus) keratitis in diabetes, we established in vivo and in vitro models of A. fumigatus keratitis, which were then exposed to high glucose. The expression levels of RvD1, 5-lipoxygenase (5-LOX), and 15-lipoxygenase (15-LOX) in A. fumigatus keratitis patients with diabetes were determined through Enzyme Linked Immunosorbent Assay (ELISA), Western blot and immunohistochemistry. Reactive Oxygen Species (ROS) production, ELISA, flow cytometry, Hematoxylin-Eosin (HE) staining and fungal loading determination were conducted to evaluate the severity of A. fumigatus infection. Lymphangiogenesis and angiogenesis were examined by immunofluorescence assay. Western blot was applied to detect the proteins of the MAPK-NF-κB pathway. The results showed that RvD1 diminished the high glucose-induced oxidative stress and inflammatory response, as evidenced by the reduction of ROS production, Interleukin-6 (IL-6), Interleukin-8 (IL-8), Heme Oxygenase-1 (HMOX-1), and the elevation of Cyclooxygenase-2 (COX2), Superoxide Dismutase (SOD-1), and Glutathione Peroxidase-2 (GPX2) levels in A. fumigatus-infected Human Corneal Endothelial Cells (HCECs). Additionally, lymphangiogenesis and angiogenesis prominently decreased after intervention with RvD1. Furthermore, RvD1 significantly reduced the levels of p-MEK1/2 and p-ERK1/2, and restrained the NF-κB and GPR32 activation. The above results showed that RvD1 protects against A. fumigatus keratitis in diabetes by suppressing oxidative stress, inflammatory response, fungal growth, and immunoreaction via modulating MAPK-NF-κB pathway. RvD1 provides clues for the therapeutic targets of Fungal keratitis complicated with diabetes.

• Authors: Qin Qin, Kai Hu, Zifang He, Feifei Chen, Wenwen Zhang, Yajun Liu, Zhenggao Xie
• Journal: Experimental eye research (Exp Eye Res) Vol. 216 Pg. 108941 (03 2022) ISSN: 1096-0007 [Electronic] England
• PMID: 35077754 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• NF-kappa B
• Reactive Oxygen Species
• resolvin D1
• Docosahexaenoic Acids
• Oxidoreductases
• Arachidonate 15-Lipoxygenase
• Arachidonate 5-Lipoxygenase
• Mitogen-Activated Protein Kinase Kinases
• Glucose

Topics

• Animals
• Arachidonate 15-Lipoxygenase (metabolism)
• Arachidonate 5-Lipoxygenase (metabolism)
• Aspergillosis (metabolism, microbiology, prevention & control)
• Aspergillus fumigatus (physiology)
• Blotting, Western
• Cells, Cultured
• Corneal Ulcer (metabolism, microbiology, prevention & control)
• Diabetes Complications (metabolism, microbiology)
• Disease Models, Animal
• Docosahexaenoic Acids (physiology)
• Enzyme-Linked Immunosorbent Assay
• Epithelium, Corneal (drug effects, microbiology)
• Eye Infections, Fungal (metabolism, microbiology, prevention & control)
• Flow Cytometry
• Glucose (pharmacology)
• Humans
• Immunohistochemistry
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• NF-kappa B (metabolism)
• Oxidative Stress (drug effects)
• Oxidoreductases (metabolism)
• Reactive Oxygen Species (metabolism)
• Mice