title: The crosstalk between TLR2 and NOD2 in Aspergillus fumigatus keratitis.
abstract: Innate immunity is considered to be critical in the pathogenesis of fungal keratitis. Pattern recognition receptors (PRRs) recognize conserved microbial structures called pathogen-associated molecular patterns (PAMPS), thereby initiating the innate immunity. Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (leucine-rich repeat-containing receptors, NLRs) are two major PRR families. The crosstalk between TLR2 and NOD2 is not completely understood, and their interrelationship in Aspergillus fumigates keratitis is still unclear. To our surprise, we found herein that NOD2 and TLR2 were increased by A. fumigatus conidia in immortalized human corneal epithelial cells (HCECs). In addition, NOD2 expression was up-regulated by its agonist muramyl dipeptide (MDP), along with receptor interacting protein 2 (RIP2), nuclear factor κB (NFκB)-p65, inhibitor of NFκB (IκB)-α, and multiple inflammatory cytokines, including interleukin-6 (IL-6), IL-8 and tumor necrosis factor α (TNF-α). Interestingly, zymosan, a TLR2 agonist, promoted the expression of NOD2 and RIP2 in a TLR2-dependent manner. Furthermore, we demonstrated that the increased expression of NOD2 and RIP2 caused by A. fumigatus conidia occurred in part through a TLR2-dependent pathway. However, zymosan pretreatment decreased NOD2 and RIP2 expression along with the MDP induced secretion of inflammatory cytokines in HCECs. In agreement, NOD2 knockdown by small interfering RNA (siRNA) reduced the release of IL-6, IL-8 and TNF-α induced by A. fumigatus conidia. These findings suggest the existence of complex interactions between TLR2 and NOD2 in HCECs inflammatory response against A. fumigatus infection.
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University, Jinan, Shandong, PR China; Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University, Jinan, Shandong, PR China; Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
authors.forename: Zhaoting
authors.initials: Z
authors.lastname: Xin
authors.affiliation: Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China. Electronic address: xywu8868@163.com.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wu
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000276:immunology*; D002461:Cell Line, Transformed; D003315:Cornea / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D000072000:NF-KappaB Inhibitor alpha; D053473:Nod2 Signaling Adaptor Protein / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013172:Spores, Fungal / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D015054:Zymosan / Q000494:pharmacology
chemical_list: D020672:I-kappa B Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; C000606204:NFKBIA protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C498143:RELA protein, human; D034741:RNA, Small Interfering; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D015054:Zymosan; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2
keywords: Aspergillus fumigatus; HCECs; NOD2; TLR2