TLR4/7-mediated host-defense responses of gingival epithelial cells.
AKT
LPS
TLR
chemokine
defensin
gingival epithelial cell
interferon
Journal
Journal of cellular biochemistry
ISSN: 1097-4644
Titre abrégé: J Cell Biochem
Pays: United States
ID NLM: 8205768
Informations de publication
Date de publication:
10 May 2024
10 May 2024
Historique:
revised:
18
04
2024
received:
12
01
2024
accepted:
25
04
2024
medline:
10
5
2024
pubmed:
10
5
2024
entrez:
10
5
2024
Statut:
aheadofprint
Résumé
Gingival epithelial cells (GECs) are physical and immunological barriers against outward pathogens while coping with a plethora of non-pathogenic commensal bacteria. GECs express several members of Toll-like receptors (TLRs) and control subsequent innate immune responses. TLR4 senses lipopolysaccharide (LPS) while TLR7/8 recognizes single-strand RNA (ssRNA) playing important roles against viral infection. However, their distinct roles in GECs have not been fully demonstrated. Here, we analyzed biological responses of GECs to LPS and CL075, a TLR7/8 agonist. GE1, a mouse gingival epithelial cell line, constitutively express TLR4 and TLR7, but not TLR8, like primary skin keratinocytes. Stimulation of GE1 cells with CL075 induced cytokine, chemokine, and antimicrobial peptide expressions, the pattern of which is rather different from that with LPS: higher mRNA levels of interferon (IFN) β, CXCL10, and β-defensin (BD) 14 (mouse homolog of human BD3); lower levels of tumor necrosis factor (TNF), CCL5, CCL11, CCL20, CXCL2, and CX3CL1. As for the intracellular signal transduction of GE1 cells, CL075 rapidly induced significant AKT phosphorylation but failed to activate IKKα/β-NFκB pathway, whereas LPS induced marked IKKα/β-NFκB activation without significant AKT phosphorylation. In contrast, both CL075 and LPS induced rapid IKKα/β-NFκB activation and AKT phosphorylation in a macrophage cell line. Furthermore, specific inhibition of AKT activity abrogated CL075-induced IFNβ, CXCL10, and BD14 mRNA expression in GE1 cells. Thus, TLR4/7 ligands appear to induce rather different host-defense responses of GECs through distinct intracellular signaling mechanisms.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Japan Society for the Promotion of Science
ID : 21K09829
Organisme : Ministry of Education, Culture, Sports, Science and Technology of Japan
Informations de copyright
© 2024 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.
Références
Hajishengallis G, Lamont RJ. Beyond the red complex and into more complexity: the polymicrobial synergy and dysbiosis (PSD) model of periodontal disease etiology. Mol Oral Microbiol. 2012;27:409‐419.
Dayakar MM, Shipilova A, Gupta D. Periodontal pocket as a potential reservoir of high risk human papilloma virus: a pilot study. J Indian Soc Periodontol. 2016;20:136‐140.
Gupta S, Mohindra R, Chauhan PK, et al. SARS‐CoV‐2 detection in gingival crevicular fluid. J Dent Res. 2021;100:187‐193.
Mardirossian A, Contreras A, Navazesh M, Nowzari H, Slots J. Herpesviruses 6, 7 and 8 in HIV‐ and non‐HIV‐associated periodontitis. J Periodont Res. 2000;35:278‐284.
Matičić M, Poljak M, Kramar B, et al. Proviral HIV‐1 DNA in gingival crevicular fluid of HIV‐1‐infected patients in various stages of HIV disease. J Dent Res. 2000;79:1496‐1501.
Groeger S, Meyle J. Oral mucosal epithelial cells. Front Immunol. 2019;10:208.
Johnstone KF, Herzberg MC. Antimicrobial peptides: defending the mucosal epithelial barrier. Front Oral Health. 2022;3:958480.
Rani L, Arora A, Majhi S, Mishra A, Mallajosyula SS. Experimental and simulation studies reveal mechanism of action of human defensin derivatives. Biochim Biophys Acta Biomembr. 2022;1864:183824.
Murakami S, Mealey BL, Mariotti A, Chapple ILC. Dental plaque‐induced gingival conditions. J Periodontol. 2018;89(suppl 1):S17‐S27.
Ma X, Ma L, Chang Q, et al. Type I interferon induced and antagonized by foot‐and‐mouth disease virus. Front Microbiol. 2018;9:1862.
Wen J, Xuan B, Liu Y, et al. NLRP3 inflammasome‐induced pyroptosis in digestive system tumors. Front Immunol. 2023;14:1074606.
Trinchieri G, Sher A. Cooperation of Toll‐like receptor signals in innate immune defence. Nat Rev Immunol. 2007;7:179‐190.
Tan Y, Kagan JC. A cross‐disciplinary perspective on the innate immune responses to bacterial lipopolysaccharide. Mol Cell. 2014;54:212‐223.
Simmons RP, Scully EP, Groden EE, et al. HIV‐1 infection induces strong production of IP‐10 through TLR7/9‐dependent pathways. AIDS. 2013;27:2505‐2517.
Zhang T, Zhu J, Su B, et al. Effects of TLR7 polymorphisms on the susceptibility and progression of HIV‐1 infection in Chinese MSM population. Front Immunol. 2020;11:589010.
Moore JS, Rahemtulla F, Kent LW, et al. Oral epithelial cells are susceptible to cell‐free and cell‐associated HIV‐1 infection in vitro. Virology. 2003;313:343‐353.
Vacharaksa A, Asrani AC, Gebhard KH, et al. Oral keratinocytes support non‐replicative infection and transfer of harbored HIV‐1 to permissive cells. Retrovirology. 2008;5:66.
Luo Z, Ge M, Chen J, et al. HRS plays an important role for TLR7 signaling to orchestrate inflammation and innate immunity upon EV71 infection. PLoS Pathog. 2017;13:e1006585.
Tian H, Xu W, Wen L, et al. Association of TLR3 gene 1377C/T (rs3775290) and TLR7 gene C/G (rs3853839) polymorphism with hand, foot, and mouth disease caused by human enterovirus 71 infection susceptibility and severity in the Chinese Han population: a meta‐analysis of case‐control studies. Medicine. 2022;101:e29758.
Lichti U, Anders J, Yuspa SH. Isolation and short‐term culture of primary keratinocytes, hair follicle populations and dermal cells from newborn mice and keratinocytes from adult mice for in vitro analysis and for grafting to immunodeficient mice. Nat Protoc. 2008;3:799‐810.
Sugimoto K, Ohata M, Miyoshi J, et al. A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA‐induced IL‐12 production and Th cell differentiation. J Clin Invest. 2004;114:857‐866.
Hatakeyama S, Ohara‐Nemoto Y, Yanai N, Obinata M, Hayashi S, Satoh M. Establishment of gingival epithelial cell lines from transgenic mice harboring temperature sensitive simian virus 40 large T‐antigen gene. J Oral Pathol Med. 2001;30:296‐304.
Matsuguchi T, Chiba N, Bandow K, Kakimoto K, Masuda A, Ohnishi T. JNK activity is essential for Atf4 expression and late‐stage osteoblast differentiation. J Bone Miner Res. 2009;24:398‐410.
Kawai T, Akira S. The role of pattern‐recognition receptors in innate immunity: update on Toll‐like receptors. Nat Immunol. 2010;11:373‐384.
Jurk M, Heil F, Vollmer J, et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R‐848. Nat Immunol. 2002;3:499.
Ma Y, Haynes RL, Sidman RL, Vartanian T. TLR8: an innate immune receptor in brain, neurons and axons. Cell Cycle. 2007;6:2859‐2868.
Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173:3916‐3924.
Kusumoto Y, Hirano H, Saitoh K, et al. Human gingival epithelial cells produce chemotactic factors interleukin‐8 and monocyte chemoattractant protein‐1 after stimulation with Porphyromonas gingivalis via toll‐like receptor 2. J Periodontol. 2004;75:370‐379.
Lebre MC, van der Aar AMG, van Baarsen L, et al. Human keratinocytes express functional Toll‐like receptor 3, 4, 5, and 9. J Invest Dermatol. 2007;127:331‐341.
Li ZJ, Sohn KC, Choi DK, et al. Roles of TLR7 in activation of NF‐kappaB signaling of keratinocytes by imiquimod. PLoS One. 2013;8:e77159.
Wang ZH, Feng Y, Hu Q, et al. Keratinocyte TLR2 and TLR7 contribute to chronic itch through pruritic cytokines and chemokines in mice. J Cell Physiol. 2023;238:257‐273.
Donetti E, Cornaghi L, Arnaboldi F, et al. Epidermal barrier reaction to an in vitro psoriatic microenvironment. Exp Cell Res. 2017;360:180‐188.
Ueda S, Goto M, Hashimoto K, et al. Salivary CCL20 level as a biomarker for oral squamous cell carcinoma. Cancer Genomics Proteomics. 2021;18:103‐112.
Schutyser E, Struyf S, Van Damme J. The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev. 2003;14:409‐426.
Ghosh M, Shen Z, Schaefer TM, Fahey JV, Gupta P, Wira CR. CCL20/MIP3α is a novel anti‐HIV‐1 molecule of the human female reproductive tract. Am J Reprod Immunol. 2009;62:60‐71.
Yang D, Chen Q, Hoover DM, et al. Many chemokines including CCL20/MIP‐3α display antimicrobial activity. J Leukoc Biol. 2003;74:448‐455.
Elemam N, Talaat I, Maghazachi A. CXCL10 chemokine: a critical player in RNA and DNA viral infections. Viruses. 2022;14:2445.
Gudowska‐Sawczuk M, Mroczko B. What is currently known about the role of CXCL10 in SARS‐CoV‐2 infection? Int J Mol Sci. 2022;23:3673.
Holly MK, Diaz K, Smith JG. Defensins in viral infection and pathogenesis. Annu Rev Virol. 2017;4:369‐391.
Drozdzik A, Drozdzik M. Oral pathology in COVID‐19 and SARS‐CoV‐2 infection‐molecular aspects. Int J Mol Sci. 2022;23:1431.
Lloyd MG, Liu D, Legendre M, Markovitz DM, Moffat JF. H84T BanLec has broad spectrum antiviral activity against human herpesviruses in cells, skin, and mice. Sci Rep. 2022;12:1641.
Rohrl J, Yang D, Oppenheim JJ, Hehlgans T. Identification and biological characterization of mouse beta‐defensin 14, the orthologue of human beta‐defensin 3. J Biol Chem. 2008;283:5414‐5419.
Weinberg A, Quiñones‐Mateu ME, Lederman MM. Role of human β‐defensins in HIV infection. Adv Dent Res. 2006;19:42‐48.
Yamamoto M, Sato S, Hemmi H, et al. Role of adaptor TRIF in the MyD88‐independent Toll‐like receptor signaling pathway. Science. 2003;301:640‐643.
Rathinam VAK, Vanaja SK, Waggoner L, et al. TRIF licenses caspase‐11‐dependent NLRP3 inflammasome activation by gram‐negative bacteria. Cell. 2012;150:606‐619.
de Marcken M, Dhaliwal K, Danielsen AC, Gautron AS, Dominguez‐Villar M. TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection. Sci Signal. 2019;12:eaaw1347.
Joung SM, Park ZY, Rani S, Takeuchi O, Akira S, Lee JY. Akt contributes to activation of the TRIF‐dependent signaling pathways of TLRs by interacting with TANK‐binding kinase 1. J Immunol. 2011;186:499‐507.
Li L, Cheng FW, Wang F, Jia B, Luo X, Zhang SQ. The activation of TLR7 regulates the expression of VEGF, TIMP1, MMP2, IL‐6, and IL‐15 in Hela cells. Mol Cell Biochem. 2014;389:43‐49.
Li Q, Yan Y, Liu J, et al. Toll‐like receptor 7 activation enhances CD8+ T cell effector functions by promoting cellular glycolysis. Front Immunol. 2019;10:2191.
Kim Y, Kim HG, Han SY, et al. Hydroquinone suppresses IFN‐β expression by targeting AKT/IRF3 pathway. Korean J Physiol Pharmacol. 2017;21:547‐554.
Callahan V, Hawks S, Crawford MA, et al. The Pro‐inflammatory chemokines CXCL9, CXCL10 and CXCL11 are upregulated following SARS‐CoV‐2 infection in an AKT‐dependent manner. Viruses. 2021;13:1062.