Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Toll-Like Receptor Signaling in the Pathogenesis of Chronic Dacryocystitis: Implication of c-FOS Transcription Factor and its Downstream Effector Chemokine Genes CCL2, CCL4, CXCL3, CXCR4 with a Shift of the M1/M2 Macrophage Phenotype

Author(s): Noha Ahmed Edris, Basma Emad Aboulhoda*, Shimaa Saad El-Din, Amina Mahmoud Fouad, Emad Albadawi, Laila Ahmed Rashed and Kareem Bakr Elessawy

Volume 26, Issue 3, 2023

Published on: 21 July, 2022

Page: [489 - 497] Pages: 9

DOI: 10.2174/1386207325666220509150457

Price: $65

Abstract

Introduction: TLRs are fundamental elements in the orchestration of the innate immune system. These receptors seem to be responsible for the inflammation and fibrosis in chronic dacryocystitis. The aim of the present study was to investigate the role of the toll-Like receptors (TLR2 and TLR4) signaling pathway and its downstream effector chemokine genes in the pathogenesis of chronic dacryocystitis.

Methods: This study was conducted on 20 patients diagnosed with chronic dacryocystitis and underwent external dacryocystorhinostomy. Estimation of gene expression of TLR2, TLR4, CCL2, CCL4, CXCL3, CXCR4, and c-FOS genes in the lacrimal sac tissues was performed together with the assessment of the inflammatory markers TNFα, IL-1β, IFN-γ, and IL-22. Histopathological examination of the lacrimal sac walls using hematoxylin and eosin (H&E) stain, in addition to immunohistochemical staining of the CD68 and CD163 macrophage markers, was also performed.

Results: Our results showed that TLR2, TLR4, and c-FOS gene expressions were significantly increased in the chronic dacryocystitis group with a subsequent increase in their downstream effector chemokine genes CCL2, CCL4, and CXCL3. This up-regulation of genes was accompanied by macrophage shift of polarization toward the M1 pro-inflammatory phenotype (increased CD68 and decreased CD163 expression), leading to increased levels of the pro-inflammatory cytokines (TNF- α, IL-1β and IFN-γ) and decreased anti-inflammatory marker IL-22 with chronic dacryocystitis.

Conclusion: It is essential to fine-tune TLR activation through emerging therapeutic approaches. Targeting TLR signaling at the level of receptors or downstream adaptor molecules represents a new challenge for treating chronic dacryocystitis.

Keywords: Toll-Like receptors, macrophage polarization, pro-inflammatory cytokines, chemokines, chronic dacryocystitis, epipjora.

« Previous Next »
Graphical Abstract

[1]
Amin, R.M.; Hussein, F.A.; Idriss, H.F.; Hanafy, N.F.; Abdallah, D.M. Pathological, immunohistochemical and microbiologicalal analysis of lacrimal sac biopsies in patients with chronic dacrocystitis. Int. J. Ophthalmol., 2013, 6(6), 817-826.
[PMID: 24392331]
[2]
Anderson, NG.; Wojno, TH.; Grossniklaus, HE. Clinicopathologic findings from lacrimal sac biopsy specimens obtained during dacryocys-torhinostomy. Ophthalmol Plast. Reconstr. Surg., 2009, 19, 173-176.
[3]
Majidaee, M.; Mohammadi, M.; Sheikh, M.R.; Khademlu, M.; Gorji, M.H. Patients undergoing dacryocystorhinostomy surgery in northern iran: an epidemiologic study. Ann. Med. Health Sci. Res., 2014, 4(3), 365-368.
[http://dx.doi.org/10.4103/2141-9248.133461] [PMID: 24971210]
[4]
Ali, M.J.; Mulay, K.; Pujari, A.; Naik, M.N. Derangements of lacrimal drainage-associated lymphoid tissue (LDALT) in human chronic dacryocystitis. Ocul. Immunol. Inflamm., 2013, 21(6), 417-423.
[http://dx.doi.org/10.3109/09273948.2013.797473] [PMID: 23924208]
[5]
Cen, X.; Liu, S.; Cheng, K. The role of toll-like receptor in inflammation and tumor immunity. Front. Pharmacol., 2018, 9, 878.
[http://dx.doi.org/10.3389/fphar.2018.00878] [PMID: 30127747]
[6]
Penttilä, E.; Hyttinen, J.M.T.; Hytti, M.; Kauppinen, A.; Smirnov, G.; Tuomilehto, H.; Seppä, J.; Nuutinen, J.; Kaarniranta, K. Upregulation of inflammatory genes in the nasal mucosa of patients undergoing endonasal dacryocystorhinostomy. Clin. Ophthalmol., 2014, 8, 799-805.
[http://dx.doi.org/10.2147/OPTH.S50195] [PMID: 24851037]
[7]
Tian, X.; Xie, G.; Xiao, H.; Ding, F.; Bao, W.; Zhang, M. CXCR4 knockdown prevents inflammatory cytokine expression in macrophages by suppressing activation of MAPK and NF-κB signaling pathways. Cell Biosci., 2019, 9(1), 1-8.
[http://dx.doi.org/10.1186/s13578-019-0315-x]
[8]
Salour, H.; Hatami, M.M.; Parvin, M.; Ferdowsi, A.A.; Abrishami, M.; Bagheri, A.; Aletaha, M.; Yazdani, S. Clinicopathological study of lacrimal sac specimens obtained during DCR. Orbit, 2010, 29(5), 250-253.
[http://dx.doi.org/10.3109/01676830.2010.485720] [PMID: 20812824]
[9]
O’Neill, L.A.; Bryant, C.E.; Doyle, S.L. Therapeutic targeting of Toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol. Rev., 2009, 61(2), 177-197.
[http://dx.doi.org/10.1124/pr.109.001073] [PMID: 19474110]
[10]
Aboulhoda, B.E.; El-Din, S.S.; Khalifa, M.M.; Arsanyos, S.F.; Motawie, A.G.; Sedeek, M.S.; Abdelfattah, G.H.; Abdelgalil, W.A. Histolog-ical, immunohistochemical, and molecular investigation on the hepatotoxic effect of potassium dichromate and the ameliorating role of Persea americana mill pulp extract. Microsc. Res. Tech., 2021, 84(10), 2434-2450.
[http://dx.doi.org/10.1002/jemt.23798] [PMID: 33908126]
[11]
Saad El-Din, S.; Rashed, L.; Medhat, E.; Emad Aboulhoda, B.; Desoky Badawy, A. Mohammed ShamsEldeen, A.; Abdelgwad, M. Active form of vitamin D analogue mitigates neurodegenerative changes in Alzheimer’s disease in rats by targeting Keap1/Nrf2 and MAPK-38p/ERK signaling pathways. Steroids, 2020, 156, 108586.
[http://dx.doi.org/10.1016/j.steroids.2020.108586]
[12]
Sadik, N.A.; Shaker, O.G.; Ghanem, H.Z.; Hassan, H.A.; Abdel-Hamid, A.H. Single-nucleotide polymorphism of Toll-like receptor 4 and interleukin-10 in response to interferon-based therapy in Egyptian chronic hepatitis C patients. Arch. Virol., 2015, 160(9), 2181-2195.
[http://dx.doi.org/10.1007/s00705-015-2493-0] [PMID: 26095186]
[13]
Lai, Y.; Gallo, R.L. Toll-like receptors in skin infections and inflammatory diseases. Mediators Inflamm., 2008, 8(3), 144-155.
[14]
Kumar, H.; Kawai, T.; Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol., 2011, 30(1), 16-34.
[http://dx.doi.org/10.3109/08830185.2010.529976] [PMID: 21235323]
[15]
Azam, S.; Jakaria, M.; Kim, I.S.; Kim, J.; Haque, M.E.; Choi, D.K. Regulation of toll-like receptor (TLR) signaling pathway by polyphenols in the treatment of age-linked neurodegenerative diseases: focus on TLR4 Signaling. Front. Immunol., 2019, 10, 1000.
[http://dx.doi.org/10.3389/fimmu.2019.01000] [PMID: 31134076]
[16]
Zhao, G.N.; Jiang, D.S.; Li, H. Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease. Biochim. Biophys. Acta, 2015, 1852(2), 365-378.
[http://dx.doi.org/10.1016/j.bbadis.2014.04.030] [PMID: 24807060]
[17]
Gay, N.J.; Symmons, M.F.; Gangloff, M.; Bryant, C.E. Assembly and localization of Toll-like receptor signalling complexes. Nat. Rev. Immunol., 2014, 14(8), 546-558.
[http://dx.doi.org/10.1038/nri3713] [PMID: 25060580]
[18]
Moresco, E.M.; LaVine, D.; Beutler, B. Toll-like receptors. Curr. Biol., 2011, 21(13), R488-R493.
[http://dx.doi.org/10.1016/j.cub.2011.05.039] [PMID: 21741580]
[19]
Ahmad, A.H.; Ismail, Z. c-fos and its consequences in pain. Malays. J. Med. Sci., 2002, 9(1), 3-8.
[PMID: 22969311]
[20]
Lee, H.; Fessler, M.B.; Qu, P.; Heymann, J.; Kopp, J.B. Macrophage polarization in innate immune responses contributing to pathogenesis of chronic kidney disease. BMC Nephrol., 2020, 21(1), 270.
[http://dx.doi.org/10.1186/s12882-020-01921-7] [PMID: 32660446]
[21]
Hodge-Dufour, J.; Marino, M.W.; Horton, M.R.; Jungbluth, A.; Burdick, M.D.; Strieter, R.M.; Noble, P.W.; Hunter, C.A.; Puré, E. Inhibi-tion of interferon γ induced interleukin 12 production: a potential mechanism for the anti-inflammatory activities of tumor necrosis factor. Proc. Natl. Acad. Sci. USA, 1998, 95(23), 13806-13811.
[http://dx.doi.org/10.1073/pnas.95.23.13806] [PMID: 9811882]
[22]
Darwich, L.; Coma, G.; Peña, R.; Bellido, R.; Blanco, E.J.; Este, J.A.; Borras, F.E.; Clotet, B.; Ruiz, L.; Rosell, A.; Andreo, F.; Parkhouse, R.M.; Bofill, M. Secretion of interferon-γ by human macrophages demonstrated at the single-cell level after costimulation with interleukin (IL)-12 plus IL-18. Immunology, 2009, 126(3), 386-393.
[http://dx.doi.org/10.1111/j.1365-2567.2008.02905.x] [PMID: 18759749]
[23]
Xue, Q.; Yan, Y.; Zhang, R.; Xiong, H. Regulation of iNOS on immune cells and its role in diseases. Int. J. Mol. Sci., 2018, 19(12), 3805.
[http://dx.doi.org/10.3390/ijms19123805] [PMID: 30501075]
[24]
Giordano, D.; Li, C.; Suthar, M.S.; Draves, K.E.; Ma, D.Y.; Gale, M., Jr; Clark, E.A. Nitric oxide controls an inflammatory-like Ly6C(hi)PDCA1+ DC subset that regulates Th1 immune responses. J. Leukoc. Biol., 2011, 89(3), 443-455.
[http://dx.doi.org/10.1189/jlb.0610329] [PMID: 21178115]
[25]
Gao, B.; Xiang, X. Interleukin-22 from bench to bedside: A promising drug for epithelial repair. Cell. Mol. Immunol., 2019, 16(7), 666-667.
[http://dx.doi.org/10.1038/s41423-018-0055-6] [PMID: 29921965]
[26]
Powell, N.; Pantazi, E.; Pavlidis, P.; Tsakmaki, A.; Li, K.; Yang, F.; Parker, A.; Pin, C.; Cozzetto, D.; Minns, D.; Stolarczyk, E.; Saveljeva, S.; Mohamed, R.; Lavender, P.; Afzali, B.; Digby-Bell, J.; Tjir-Li, T.; Kaser, A.; Friedman, J.; MacDonald, T.T.; Bewick, G.A.; Lord, G.M. Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells. Gut, 2020, 69(3), 578-590.
[http://dx.doi.org/10.1136/gutjnl-2019-318483] [PMID: 31792136]
[27]
El-Zayat, S.R.; Sibaii, H.; Mannaa, F.A. Toll-like receptors activation, signaling, and targeting; an overview. Bull. Natl. Res. Cent., 2019, 43(1), 187.
[http://dx.doi.org/10.1186/s42269-019-0227-2]
[28]
Cochet, F.; Peri, F. The role of carbohydrates in the lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signalling. Int. J. Mol. Sci., 2017, 18(11), 2318.
[http://dx.doi.org/10.3390/ijms18112318] [PMID: 29099761]
[29]
Schnare, M.; Rollinghoff, M.; Qureshi, S. Toll-like receptors: sentinels of host defence against bacterial infection. Int. Arch. Allergy Immunol., 2006, 139(1), 75-85.
[http://dx.doi.org/10.1159/000090001] [PMID: 16319494]
[30]
Meng, G.; Rutz, M.; Schiemann, M.; Metzger, J.; Grabiec, A.; Schwandner, R.; Luppa, P.B.; Ebel, F.; Busch, D.H.; Bauer, S.; Wagner, H.; Kirschning, C.J. Antagonistic antibody prevents toll-like receptor 2-driven lethal shock-like syndromes. J. Clin. Invest., 2004, 113(10), 1473-1481.
[http://dx.doi.org/10.1172/JCI20762] [PMID: 15146245]
[31]
Spyvee, M.R.; Zhang, H.; Hawkins, L.D.; Chow, J.C. Toll-like receptor 2 antagonists. Part 1: preliminary SAR investigation of novel syn-thetic phospholipids. Bioorg. Med. Chem. Lett., 2005, 15(24), 5494-5498.
[http://dx.doi.org/10.1016/j.bmcl.2005.08.080] [PMID: 16236498]
[32]
Spiller, S.; Elson, G.; Ferstl, R.; Dreher, S.; Mueller, T.; Freudenberg, M.; Daubeuf, B.; Wagner, H.; Kirschning, C.J. TLR4-induced IFN-gamma production increases TLR2 sensitivity and drives gram-negative sepsis in mice. J. Exp. Med., 2008, 205(8), 1747-1754.
[http://dx.doi.org/10.1084/jem.20071990] [PMID: 18644971]
[33]
Huebener, P.; Schwabe, R.F. Regulation of wound healing and organ fibrosis by toll-like receptors. Biochim. Biophys. Acta, 2013, 1832(7), 1005-1017.
[http://dx.doi.org/10.1016/j.bbadis.2012.11.017] [PMID: 23220258]

Rights & Permissions Print Cite
Article Metrics
1
© 2024 Bentham Science Publishers | Privacy Policy