Thymol Ameliorates Aspergillus fumigatus Keratitis by Downregulating the TLR4/ MyD88/ NF-kB/ IL-1β Signal Expression and Reducing Necroptosis and Pyroptosis
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Fungal keratitis is a refractory kind of keratopathy. We attempted to investigate the antiinflammatory role of thymol on Aspergillus fumigatus (A. fumigatus) keratitis. Wound healing and fluorescein staining of the cornea were applied to verify thymol’s safety. Mice models of A. fumigatus keratitis underwent subconjunctival injection of thymol. The anti-inflammatory roles of thymol were verified by hematoxylin-eosin (HE) staining, slit lamp observation, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. In contrast with the DMSO group, more transparent corneas and less inflammatory cells infiltration were detected in mice treated with 50 μg/ml thymol. Thymol downregulated the synthesis of TLR4, MyD88, NF-kB, IL-1β, NLRP3, caspase 1, caspase 8, GSDMD, RIPK3 and MLKL. In summary, we proved that thymol played a protective part in A. fumigatus keratitis by cutting down inflammatory cells aggregation, downregulating the TLR4/ MyD88/ NF-kB/ IL-1β signal expression and reducing necroptosis and pyroptosis.
Abstract
Fungal keratitis is a refractory kind of keratopathy. We attempted to investigate the antiinflammatory role of thymol on Aspergillus fumigatus (A. fumigatus) keratitis. Wound healing and fluorescein staining of the cornea were applied to verify thymol’s safety. Mice models of A. fumigatus keratitis underwent subconjunctival injection of thymol. The anti-inflammatory roles of thymol were verified by hematoxylin-eosin (HE) staining, slit lamp observation, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. In contrast with the DMSO group, more transparent corneas and less inflammatory cells infiltration were detected in mice treated with 50 μg/ml thymol. Thymol downregulated the synthesis of TLR4, MyD88, NF-kB, IL-1β, NLRP3, caspase 1, caspase 8, GSDMD, RIPK3 and MLKL. In summary, we proved that thymol played a protective part in A. fumigatus keratitis by cutting down inflammatory cells aggregation, downregulating the TLR4/ MyD88/ NF-kB/ IL-1β signal expression and reducing necroptosis and pyroptosis.
참고문헌 (42)
- Hoffman JJ, "Mycotic keratitis-A global threat from the Filamentous fungi", J. Fungi (Basel, Switzerland), 7 (2021)
- Ahmadikia K, "Distribution, prevalence, and causative agents of fungal keratitis: A systematic review and meta-analysis (1990 to 2020)", Front. Cell Infect. Microbiol, 11, pp.698780~ (2021)
- Niu L, "Fungal keratitis: pathogenesis, diagnosis and prevention", Microb. Pathog, 138, pp.103802~ (2020)
- Zhao W, "Fenretinide inhibits neutrophil recruitment and IL-1β production in Aspergillus fumigatus keratitis", Cornea, 37, pp.1579~1585
- Vandenabeele P, "Molecular mechanisms of necroptosis: an ordered cellular explosion", Nat. Rev. Mol. Cell Biol, 11, pp.700~714 (2010)
- Karmakar M, "Neutrophil IL-1β processing induced by pneumolysin is mediated by the NLRP3", ASC inflammasome and caspase-1 activation and is dependent on K+ efflux, 2015, pp.194, 1763~1775
- Wang LM, "Thymol protects against Aspergillus Fumigatus keratitis by inhibiting the LOX-1", IL-1β signaling pathway, 2022, pp.42, 620~628
- Jeong JH, "Effect of resistance exercise on muscle metabolism and autophagy in sIBM", Med. Sci. Sports Exerc, 49, pp.1562~1571 (2017)
- Burdette BE, "Gasdermin D in pyroptosis", Acta Pharm. Sin B, 11, pp.2768~2782 (2021)
- Pasparakis M, "Necroptosis and its role in inflammation", Nature, 517, pp.311~320 (2015)
- Ratitong B, "Pathogenic Aspergillus and Fusarium as important causes of blinding corneal infections - the role of neutrophils in fungal killing, tissue damage and cytokine production", Curr. Opin. Microbiol, 63, pp.195~203 (2021)
- Jain V, "Aspergillus keratitis in vernal shield ulcer--a case report and review", Int. Ophthalmol, 30, pp.641~644 (2010)
- Keay LJ, "Clinical and microbiological characteristics of fungal keratitis in the United States, 2001-2007: a multicenter study", Ophthalmology, 118, pp.920~926 (2011)
- Anane S, "Keratomycosis in the area of Tunis: epidemiological data, diagnostic and therapeutic modalities", Ann. Biol. Clin. (Paris), 68, pp.441~447 (2010)
- Ansari Z, "Current thoughts in fungal keratitis: diagnosis and treatment", Curr. Fungal Infect. Rep, 7, pp.209~218 (2013)
- Ting DSJ, "Host defense peptides at the ocular surface: Roles in health and major diseases, and therapeutic potentials", Front. Med. (Lausanne), 9, pp.835843~ (2022)
- Chai LY, "Aspergillus fumigatus cell wall components differentially modulate host TLR2 and TLR4 responses", Microbes Infect, 13, pp.151~159 (2011)
- Dai C, "Interactions of thymic stromal lymphopoietin with TLR2 and TLR4 regulate anti-fungal innate immunity in Aspergillus fumigatus-induced corneal infection", Exp. Eye Res, 182, pp.19~29 (2019)
- Johnson AC, "Activation of toll-like receptor (TLR)2, TLR4, and TLR9 in the mammalian cornea induces MyD88-dependent corneal inflammation", Invest. Ophthalmol. Vis. Sci, 46, pp.589~595 (2005)
- Akhter N, "TLR4", MyD88 -mediated CCL2 production by lipopolysaccharide (endotoxin): implications for metabolic inflammation, 2018, pp.17, 77~84
- Sozzani S, "Chemokines: a superfamily of chemotactic cytokines", Int. J. Clin. Lab. Res, 26, pp.69~82 (1996)
- Broz P, "Inflammasomes: mechanism of assembly, regulation and signalling", Nat. Rev. Immunol, 16, pp.407~420 (2016)
- Lamkanfi M, "Inflammasomes: guardians of cytosolic sanctity", Immunol. Rev, 227, pp.95~105 (2009)
- Al Mamun A, "Role of pyroptosis in spinal cord injury and its therapeutic implications", J. Adv. Res, 28, pp.97~109 (2021)
- Chow SH, "Macrophage cell death in microbial infections", Cell Microbiol, 18, pp.466~474 (2016)
- Stephenson HN, "Beyond the grave: When is cell death critical for immunity to infection?", Curr. Opin. Immunol, 38, pp.59~66 (2016)
- Rock KL, "Innate and adaptive immune responses to cell death", Immunol. Rev, 243, pp.191~205 (2011)
- Black RA, "Generation of biologically active interleukin-1beta by proteolytic cleavage of the inactive precursor", J. Biol. Chem, 263, pp.9437~9442 (1988)
- Mehta VB, "ATP-stimulated release of interleukin (IL)-1beta and IL-18 requires priming by lipopolysaccharide and is independent of caspase-1 cleavage", J. Biol. Chem, 276, pp.3820~3826 (2001)
- Yi YS, "Regulatory Roles of flavonoids on inflammasome activation during inflammatory responses", Mol. Nutr. Food Res, 62, pp.e1800147~ (2018)
- Eltom S, "TLR4 activation induces IL-1β release via an IPAF dependent but caspase 1", 11, Respir. Res, pp.2014, 15[DOI]
- Bossaller L, "Cutting edge: FAS (CD95) mediates noncanonical IL-1β and IL-18 maturation via caspase-8 in an RIP3-independent manner", J. Immunol, 189, pp.5508~5512 (2012)
- Pauwels NS, "Role of IL-1α and the Nlrp3", caspase-1, Eur. Respir. J, pp.2011, 38[DOI]
- Shi J, "Pyroptosis: Gasdermin-mediated programmed necrotic cell death", Trends Biochem. Sci, 42, pp.245~254 (2017)
- Shi J, "Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death", Nature, 526, pp.660~665 (2015)
- Van Opdenbosch N, "Caspases in cell death, inflammation, and disease", Immunity, 50, pp.1352~1364 (2019)
- Chi W, "Caspase-8 promotes NLRP1", NLRP3 inflammasome activation and IL-1βproduction in acute glaucoma, 2014, pp.111, 11181~11186
- Mulay SR, "Cytotoxicity of crystals involves RIPK3-MLKLmediated necroptosis", Nat. Commun, 7, pp.10274~ (2016)
- Wang B, "Selenomethionine alleviates LPS-induced JNK", NLRP3 inflammasome-dependent necroptosis by modulating miR-15a and oxidative stress in chicken lungs, 2021, pp.13, mfa048~
- Conos SA, "Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner", Proc. Natl. Acad. Sci. USA, 114, pp.E961~E969 (2017)
- Liu L, "Role of necroptosis in infection-related, immune-mediated, and autoimmune skin diseases", J. Dermatol, 48, pp.1129~1138 (2021)
- Liu S, "MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis", Proc. Natl. Acad. Sci. USA, 114, pp.E7450~E7459 (2017)
