{"title":"卡他列汀能增强中性粒细胞的抗真菌活性,改善曲霉菌角膜炎的预后。","authors":"Xiaochen Hou, Cui Li, Jingyi Liu, Shanshan Yang, Xudong Peng, Qian Wang, Chengxiu Liu, Xing Liu, Junjie Luan, Guiqiu Zhao, Jing Lin","doi":"10.1128/iai.00483-23","DOIUrl":null,"url":null,"abstract":"<p><p><i>Aspergillus fumigatus</i> (<i>A. fumigatus</i>) is one of the common pathogens of fungal keratitis. Fungal growth and invasion cause excessive inflammation and corneal damage, leading to severe vision loss. Neutrophils are the primary infiltrating cells critical for fungal clearance. Cathelicidin [LL-37 in humans and cathelicidin-related antimicrobial peptide (CRAMP) in mice], a natural antimicrobial peptide, can directly inhibit the growth of many pathogens and regulate immune responses. However, the role of cathelicidin and its effect on neutrophils in <i>A. fumigatus</i> keratitis remain unclear. By establishing <i>A. fumigatus</i> keratitis mouse models, we found that cathelicidin was increased in <i>A. fumigatus</i> keratitis. It could reduce fungal loads, lower clinical scores, and improve corneal transparency. Restriction of CRAMP on fungal proliferation was largely counteracted in <i>CD18<sup>-/-</sup></i> mice, in which neutrophils cannot migrate into infected sites. When WT neutrophils were transferred into <i>CD18<sup>-/-</sup></i> mice, corneal fungal loads were distinctly reduced, indicating that neutrophils are vital for CRAMP-mediated resistance. Furthermore, cathelicidin promoted neutrophils to phagocytose and degrade conidia both <i>in vitro</i> and <i>in vivo</i>. CXC chemokine receptor 2 (CXCR2) was reported to be a functional receptor of LL-37 on neutrophils. CXCR2 antagonist SB225002 or phospholipase C (PLC) inhibitor U73122 weakened LL-37-induced phagocytosis. Meanwhile, LL-37 induced PLC γ phosphorylation, which was attenuated by SB225002. SB225002 or the autophagy inhibitors Bafilomycin-A1 and 3-Methyladenine weakened LL-37-induced degradation of conidia. Transmission electron microscopy (TEM) observed that LL-37 increased autophagosomes in <i>Aspergillus</i>-infected neutrophils. Consistently, LL-37 elevated autophagy-associated protein expressions (Beclin-1 and LC3-II), but this effect was weakened by SB225002. Collectively, cathelicidin reduces fungal loads and improves the prognosis of <i>A. fumigatus</i> keratitis. Both <i>in vitro</i> and <i>in vivo</i>, cathelicidin promotes neutrophils to phagocytose and degrade conidia. LL-37/CXCR2 activates PLC γ to amplify neutrophils' phagocytosis and induces autophagy to eliminate intracellular conidia.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":null,"pages":null},"PeriodicalIF":2.9000,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11003229/pdf/","citationCount":"0","resultStr":"{\"title\":\"Cathelicidin boosts the antifungal activity of neutrophils and improves prognosis during <i>Aspergillus fumigatus</i> keratitis.\",\"authors\":\"Xiaochen Hou, Cui Li, Jingyi Liu, Shanshan Yang, Xudong Peng, Qian Wang, Chengxiu Liu, Xing Liu, Junjie Luan, Guiqiu Zhao, Jing Lin\",\"doi\":\"10.1128/iai.00483-23\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><i>Aspergillus fumigatus</i> (<i>A. fumigatus</i>) is one of the common pathogens of fungal keratitis. Fungal growth and invasion cause excessive inflammation and corneal damage, leading to severe vision loss. Neutrophils are the primary infiltrating cells critical for fungal clearance. Cathelicidin [LL-37 in humans and cathelicidin-related antimicrobial peptide (CRAMP) in mice], a natural antimicrobial peptide, can directly inhibit the growth of many pathogens and regulate immune responses. However, the role of cathelicidin and its effect on neutrophils in <i>A. fumigatus</i> keratitis remain unclear. By establishing <i>A. fumigatus</i> keratitis mouse models, we found that cathelicidin was increased in <i>A. fumigatus</i> keratitis. It could reduce fungal loads, lower clinical scores, and improve corneal transparency. Restriction of CRAMP on fungal proliferation was largely counteracted in <i>CD18<sup>-/-</sup></i> mice, in which neutrophils cannot migrate into infected sites. When WT neutrophils were transferred into <i>CD18<sup>-/-</sup></i> mice, corneal fungal loads were distinctly reduced, indicating that neutrophils are vital for CRAMP-mediated resistance. Furthermore, cathelicidin promoted neutrophils to phagocytose and degrade conidia both <i>in vitro</i> and <i>in vivo</i>. CXC chemokine receptor 2 (CXCR2) was reported to be a functional receptor of LL-37 on neutrophils. CXCR2 antagonist SB225002 or phospholipase C (PLC) inhibitor U73122 weakened LL-37-induced phagocytosis. Meanwhile, LL-37 induced PLC γ phosphorylation, which was attenuated by SB225002. SB225002 or the autophagy inhibitors Bafilomycin-A1 and 3-Methyladenine weakened LL-37-induced degradation of conidia. Transmission electron microscopy (TEM) observed that LL-37 increased autophagosomes in <i>Aspergillus</i>-infected neutrophils. Consistently, LL-37 elevated autophagy-associated protein expressions (Beclin-1 and LC3-II), but this effect was weakened by SB225002. Collectively, cathelicidin reduces fungal loads and improves the prognosis of <i>A. fumigatus</i> keratitis. Both <i>in vitro</i> and <i>in vivo</i>, cathelicidin promotes neutrophils to phagocytose and degrade conidia. LL-37/CXCR2 activates PLC γ to amplify neutrophils' phagocytosis and induces autophagy to eliminate intracellular conidia.</p>\",\"PeriodicalId\":13541,\"journal\":{\"name\":\"Infection and Immunity\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2024-04-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11003229/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Infection and Immunity\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1128/iai.00483-23\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/3/19 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Infection and Immunity","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1128/iai.00483-23","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/19 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Cathelicidin boosts the antifungal activity of neutrophils and improves prognosis during Aspergillus fumigatus keratitis.
Aspergillus fumigatus (A. fumigatus) is one of the common pathogens of fungal keratitis. Fungal growth and invasion cause excessive inflammation and corneal damage, leading to severe vision loss. Neutrophils are the primary infiltrating cells critical for fungal clearance. Cathelicidin [LL-37 in humans and cathelicidin-related antimicrobial peptide (CRAMP) in mice], a natural antimicrobial peptide, can directly inhibit the growth of many pathogens and regulate immune responses. However, the role of cathelicidin and its effect on neutrophils in A. fumigatus keratitis remain unclear. By establishing A. fumigatus keratitis mouse models, we found that cathelicidin was increased in A. fumigatus keratitis. It could reduce fungal loads, lower clinical scores, and improve corneal transparency. Restriction of CRAMP on fungal proliferation was largely counteracted in CD18-/- mice, in which neutrophils cannot migrate into infected sites. When WT neutrophils were transferred into CD18-/- mice, corneal fungal loads were distinctly reduced, indicating that neutrophils are vital for CRAMP-mediated resistance. Furthermore, cathelicidin promoted neutrophils to phagocytose and degrade conidia both in vitro and in vivo. CXC chemokine receptor 2 (CXCR2) was reported to be a functional receptor of LL-37 on neutrophils. CXCR2 antagonist SB225002 or phospholipase C (PLC) inhibitor U73122 weakened LL-37-induced phagocytosis. Meanwhile, LL-37 induced PLC γ phosphorylation, which was attenuated by SB225002. SB225002 or the autophagy inhibitors Bafilomycin-A1 and 3-Methyladenine weakened LL-37-induced degradation of conidia. Transmission electron microscopy (TEM) observed that LL-37 increased autophagosomes in Aspergillus-infected neutrophils. Consistently, LL-37 elevated autophagy-associated protein expressions (Beclin-1 and LC3-II), but this effect was weakened by SB225002. Collectively, cathelicidin reduces fungal loads and improves the prognosis of A. fumigatus keratitis. Both in vitro and in vivo, cathelicidin promotes neutrophils to phagocytose and degrade conidia. LL-37/CXCR2 activates PLC γ to amplify neutrophils' phagocytosis and induces autophagy to eliminate intracellular conidia.
期刊介绍:
Infection and Immunity (IAI) provides new insights into the interactions between bacterial, fungal and parasitic pathogens and their hosts. Specific areas of interest include mechanisms of molecular pathogenesis, virulence factors, cellular microbiology, experimental models of infection, host resistance or susceptibility, and the generation of innate and adaptive immune responses. IAI also welcomes studies of the microbiome relating to host-pathogen interactions.