Rapamycin inhibits corneal inflammatory response and neovascularization in a mouse model of corneal alkali burn

• Published in: Experimental eye research 2023-08, Vol.233, p.109539-109539, Article 109539
• Main Authors: Li, Jiande, Han, Jiangyuan, Shi, Yongpeng, Liu, Minrui
• Format: Article
• Language: English
• Subjects: Alkalies - toxicity; Animals; Burns, Chemical - metabolism; Cornea; Cornea - metabolism; Corneal Injuries - metabolism; Corneal Neovascularization - metabolism; Cytokines - metabolism; Disease Models, Animal; Eye Burns - chemically induced; Eye Burns - drug therapy; Eye Burns - pathology; Inflammation; Inflammation - metabolism; Matrix Metalloproteinase 2 - metabolism; Mice; Neovascularization; Neovascularization, Pathologic - metabolism; Rapamycin; Sirolimus - pharmacology; Sirolimus - therapeutic use; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2023.109539

Alkali burn-induced corneal injury often causes inflammation and neovascularization and leads to compromised vision. We previously reported that rapamycin ameliorated corneal injury after alkali burns by methylation modification. In this study, we aimed to investigate the rapamycin-medicated mechanism against corneal inflammation and neovascularization. Our data showed that alkali burn could induce a range of different inflammatory response, including a stark upregulation of pro-inflammatory factor expression and an increase in the infiltration of myeloperoxidase- and F4/80-positive cells from the corneal limbus to the central stroma. Rapamycin effectively downregulated the mRNA expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), toll-like receptor 4 (TLR4), nucleotide binding oligomerization domain-like receptors (NLR) family pyrin domain-containing 3 (NLRP3), and Caspase-1, and suppressed the infiltration of neutrophils and macrophages. Inflammation-related angiogenesis mediated by matrix metalloproteinase-2 (MMP-2) and rapamycin restrained this process by inhibiting the TNF-α upregulation in burned corneas of mice. Rapamycin also restrained corneal alkali burn-induced inflammation by regulating HIF-1α/VEGF-mediated angiogenesis and the serum cytokines TNF-α, IL-6, Interferon-gamma (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The findings of this study indicated rapamycin may reduce inflammation-associated infiltration of inflammatory cells, shape the expression of cytokines, and balance the regulation of MMP-2 and HIF-1α-mediated inflammation and angiogenesis by suppressing mTOR activation in corneal wound healing induced by an alkali injury. It offered novel insights relevant for a potent drug for treating corneal alkali burn. •Alkali burn induces infiltration of inflammatory cells from corneal limbus to the center following alkali burn.•Corneal alkali burn induces a range of different inflammatory response involving different inflammatory cytokines and cells, and rapamycin inhibits this process.•MMP-2 mediated inflammation-related angiogenesis and rapamycin restrains this process by inhibiting TNF-α upregulation.•Rapamycin is effective in inhibiting serum cytokines TNF-α, IFN-γ and GM-CSF secretion after alkali burn.•Rapamycin may balance the regulation of MMP-2 and HIF-1α-mediated inflammation and angiogenesis by suppressing mTOR activation