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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2022

Open Access 01-12-2022 | Cytokines | Research

Immunological status of the olfactory bulb in a murine model of Toll-like receptor 3-mediated upper respiratory tract inflammation

Authors: Ryoji Kagoya, Makiko Toma-Hirano, Junya Yamagishi, Naoyuki Matsumoto, Kenji Kondo, Ken Ito

Published in: Journal of Neuroinflammation | Issue 1/2022

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Abstract

Background

Postviral olfactory dysfunction (PVOD) following a viral upper respiratory tract infection (URI) is one of the most common causes of olfactory disorders, often lasting for over a year. To date, the molecular pathology of PVOD has not been elucidated.

Methods

A murine model of Toll-like receptor 3 (TLR3)-mediated upper respiratory tract inflammation was used to investigate the impact of URIs on the olfactory system. Inflammation was induced via the intranasal administration of polyinosinic–polycytidylic acid (poly(I:C), a TLR3 ligand) to the right nostril for 3 days. Peripheral olfactory sensory neurons (OSNs), immune cells in the olfactory mucosa, and glial cells in the olfactory bulb (OB) were analyzed histologically. Proinflammatory cytokines in the nasal tissue and OB were evaluated using the quantitative real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA).

Results

In the treated mice, OSNs were markedly reduced in the olfactory mucosa, and T cell and neutrophil infiltration therein was observed 1 day after the end of poly(I:C) administration. Moreover, there was a considerable increase in microglial cells and slight increase in activated astrocytes in the OB. In addition, qPCR and ELISA revealed the elevated expression of interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma both in the OB and nasal tissue.

Conclusions

Taken together, the decreased peripheral OSNs, OB microgliosis, and elevated proinflammatory cytokines suggest that immunological changes in the OB may be involved in the pathogenesis of PVOD.
Literature
1.
2.
3.
Tan KS, Yan Y, Ong HH, Chow VTK, Shi L, Wang DY. Impact of respiratory virus infections in exacerbation of acute and chronic rhinosinusitis. Curr Allergy Asthma Rep. 2017;17:24.PubMedPubMedCentralCrossRef
4.
Rombaux P, Huart C, Collet S, Eloy P, Negoias S, Hummel T. Presence of olfactory event-related potentials predicts recovery in patients with olfactory loss following upper respiratory tract infection. Laryngoscope. 2010;120:2115–8.PubMedCrossRef
5.
6.
Jafek BW, Murrow B, Michaels R, Restrepo D, Linschoten M. Biopsies of human olfactory epithelium. Chem Senses. 2002;27:623–8.PubMedCrossRef
7.
Yamagishi M, Fujiwara M, Nakamura H. Olfactory mucosal findings and clinical course in patients with olfactory disorders following upper respiratory viral infection. Rhinology. 1994;32:113–8.PubMed
8.
Kim YK, Hong SL, Yoon EJ, Kim SE, Kim J-W. Central presentation of postviral olfactory loss evaluated by positron emission tomography scan: a pilot study. Am J Rhinol Allergy. 2012;26:204–8.PubMedCrossRef
9.
Kanaya K, Kondo K, Suzukawa K, et al. Innate immune responses and neuroepithelial degeneration and regeneration in the mouse olfactory mucosa induced by intranasal administration of Poly(I:C). Cell Tissue Res. 2014;357:279–99.PubMedPubMedCentralCrossRef
10.
Akira S, Hemmi H. Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett. 2003;85:85–95.PubMedCrossRef
11.
Matsumoto M, Seya T. TLR3: interferon induction by double-stranded RNA including poly(I:C). Adv Drug Deliv Rev. 2008;60:805–12.PubMedCrossRef
12.
13.
Tengroth L, Millrud CR, Kvarnhammar AM, KumlienGeorén S, Latif L, Cardell LO. Functional effects of Toll-Like Receptor (TLR)3, 7, 9, RIG-I and MDA-5 stimulation in nasal epithelial cells. PLoS ONE. 2014;9:e98239.PubMedPubMedCentralCrossRef
14.
Murtaza M, Chacko A, Delbaz A, Reshamwala R, Rayfield A, McMonagle B, St John JA, Ekberg JAK. Why are olfactory ensheathing cell tumors so rare? Cancer Cell Int. 2019;19:260.PubMedPubMedCentralCrossRef
15.
Reden J, Mueller A, Mueller C, Konstantinidis I, Frasnelli J, Landis BN, Hummel T. Recovery of olfactory funcion following closed head injury or infections of the upper respiratory tract. Arch Otolaryngol Head Neck Surg. 2006;132:265–9.PubMedCrossRef
16.
Duncun HJ, Seiden AM. Long-term follow-up of olfactory loss secondary to head trauma and upper respiratory tract infection. Arch Otolaryngol Head Neck Surg. 1995;121:1183–7.CrossRef
17.
Doorn KJ, Goudriaan A, Blits-Huizinga C, Bol JG, Rozemuller AJ, Hoogland PV, Lucassen PJ, Drukarch B, van de Berg WD, van Dam AM. Increased amoeboid microglial density in the olfactory bulb of Parkinson’s and Alzheimer’s patients. Brain Pathol. 2014;24:152–65.PubMedCrossRef
18.
Reale M, D’Angelo C, Costantini E, Di Nicola M, Yarla NS, Kamal MA, Salvador N, Perry G. Expression profiling of cytokine, cholinergic markers, and amyloid-beta deposition in the APPSWE/PS1dE9 mouse model of Alzheimer’s disease pathology. J Alzheimers Dis. 2018;62:467–76.PubMedPubMedCentralCrossRef
19.
Yang M, Crawley JN. Simple behavioral assessment of mouse olfaction. Curr Protoc Neurosci. 2009;8:8–24 (Buried food testのcitation).
20.
Martin E, El-Behi M, Fontaine B, Delarasse C. Analysis of microglia and monocyte-derived macrophages from the central nervous system by flow cytometry. J Vis Exp. 2017;124:55781.
21.
Kobayashi M, Tamari K, Al Salihi MO, Nishida K, Takeuchi K. Anti-high mobility group box 1 antibody suppresses local inflammatory reaction and facilitates olfactory nerve recovery following injury. J Neuroinflamm. 2018;15:124.CrossRef
22.
Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA. Microglia recognize double-strand RNA via TLR3. J Immunol. 2006;176:3804–12.PubMedCrossRef
23.
Durrant DM, Ghosh S, Klein RS. The olfactory bulb: an immunosensory effector organ during neurotropic viral infections. ACS Chem Neurosci. 2016;7:464–9.PubMedCrossRef
24.
Xie L, Zhang N, Zhang Q, Li C, Sandhu AF, Iii GW, Lin S, Lv P, Liu Y, Wu Q, Yu S. Inflammatory factors and amyloid beta-induced microglial polarization promote inflammatory crosstalk with astrocytes. Aging (Albany NY). 2020;12:22538–49.
25.
Pascual O, Ben Achour S, Rostaing P, Triller A, Bessis A. Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci USA. 2012;109:E197-205.PubMedCrossRef
26.
Wang J, Liu J, Zhou R, Ding X, Zhang Q, Zhang C, Li L. Zika virus infected primary microglia impairs NPCs proliferation and differentiation. Biochem Biophys Res Commun. 2018;497:619–25.PubMedCrossRef
27.
Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci. 2007;10:1538–43.PubMedCrossRef
28.
29.
Lehnardt S. Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia. 2010;58:253–63.PubMed
30.
Almolda B, de Labra C, Barrera I, Gruart A, Delgado-Garcia JM, Villacampa N, Vilella A, Hofer MJ, Hidalgo J, Campbell IL, González B, Castellano B. Alterations in microglial phenotype and hippocampal neuronal function in transgenic mice with astrocyte-targeted production of interleukin-10. Brain Behav Immun. 2015;45:80–97.PubMedCrossRef
31.
Li Z, Ma L, Kulesskaya N, Võikar V, Tian L. Microglia are polarized to M1 type in high-anxiety inbred mice in response to lipopolysaccharide challenge. Brain Behav Immun. 2014;38:237–48.PubMedCrossRef
32.
Prajeeth CK, Löhr K, Floess S, Zimmermann J, Ulrich R, Gudi V, et al. Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia. Brain Behav Immun. 2014;37:248–59.PubMedCrossRef
33.
Honjoh K, Nakajima H, Hirai T, Watanabe S, Matsumine A. Relationship of inflammatory cytokines from M1-type microglia/macrophages at the injured site and lumbar enlargement with neuropathic pain after spinal cord injury in the CCL21 knockout (plt) mouse. Front Cell Neurosci. 2019;13:525.PubMedPubMedCentralCrossRef
34.
Zhang J, Xie X, Tang M, Zhang J, Zhang B, Zhao Q, Han Y, Yan W, Peng C, You Z. Salvianolic acid B promotes microglial M2-polarization and rescues neurogenesis in stressexposed mice. Brain Behav Immun. 2017;66:111–24.PubMedCrossRef
35.
Al Salihi MO, Kobayashi M, Tamari K, Miyamura T, Takeuchi K. Tumor necrosis factor-alpha antagonist suppresses local inflammatory reaction and facilitates olfactory nerve recovery following injury. Auris Nasus Larynx. 2017;44:70–8.PubMedCrossRef
36.
Kobayashi M, Tamari K, Miyamura T, Takeuchi K. Blockade of interleukin-6 receptor suppresses inflammatory reaction and facilitates functional recovery following olfactory system injury. Neurosci Res. 2013;76:125–32.PubMedCrossRef
37.
Pozharskaya T, Lane AP. Interferon gamma causes olfactory dysfunction without concomitant neuroepithelial damage. Int Forum Allergy Rhinol. 2013;3:861–5.PubMedCrossRef
38.
Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C, Feldmann M, Takata M, Lever IJ, Nanchahal J, Fanselow MS, Maze M. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol. 2010;68:360–8.PubMedPubMedCentralCrossRef
39.
Ghosh M, Xu Y, Pearse DD. Cyclic AMP is a key regulator of M1 to M2a phenotypic conversion of microglia in the presence of Th2 cytokines. J Neuroinflamm. 2016;13:9.CrossRef
40.
Franco R, Fernández-Suárez D. Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol. 2015;131:65–86.PubMedCrossRef
41.
Hasegawa-Ishii S, Shimada A, Imamura F. Lipopolysaccharide-initiated persistent rhinitis causes gliosis and synaptic loss in the olfactory bulb. Sci Rep. 2017;7:11605.PubMedPubMedCentralCrossRef
42.
Hasegawa-Ishii S, Shimada A, Imamura F. Neuroplastic changes in the olfactory bulb associated with nasal inflammation in mice. J Allergy Clin Immunol. 2019;143:978-989.e3.PubMedCrossRef
43.
Herbert RP, Harris J, Chong KP, Chapman J, West AK, Chuah MI. Cytokines and olfactory bulb microglia in response to bacterial challenge in the compromised primary olfactory pathway. J Neuroinflamm. 2012;9:109.CrossRef
44.
Maelfait J, Vercammen E, Janssens S, Schotte P, Haegman M, Magez S, Beyaert R. Stimulation of Toll-like receptor 3 and 4 induces interleukin-1beta maturation by caspase-8. J Exp Med. 2008;205:1967–73.PubMedPubMedCentralCrossRef
45.
Stowell NC, Seideman J, Raymond HA, Smalley KA, Lamb RJ, Egenolf DD, Bugelski PJ, Murray LA, Marsters PA, Bunting RA, Flavell RA, Alexopoulou L, San Mateo LR, Griswold DE, Sarisky RT, Mbow ML, Das AM. Long-term activation of TLR3 by poly(I:C) induces inflammation and impairs lung function in mice. Respir Res. 2009;10:43.PubMedPubMedCentralCrossRef
46.
Ramezanpour M, Bolt H, Psaltis AJ, Wormald PJ, Vreugde S. Primary human nasal epithelial cells: a source of poly (I:C) LMW-induced IL-6 production. Sci Rep. 2018;8:11325.PubMedPubMedCentralCrossRef
47.
Zhao J, Wohlford-Lenane C, Zhao J, Fleming E, Lane TE, McCray PB Jr, Perlman S. Intranasal treatment with poly(IC) protects aged mice from lethal respiratory virus infections. J Virol. 2012;86:11416–24.PubMedPubMedCentralCrossRef
48.
Dantzer R. Cytokine, sickness behavior, and depression. Immunol Allergy Clin N Am. 2009;29:247–64.CrossRef
49.
Konsman JP, Luheshi GN, Bluthe RM, Dantzer R. The vagus nerve mediates behavioural depression, but not fever, in response to peripheral immune signals; a functional anatomical analysis. Eur J Neurosci. 2000;12:4434–46.PubMedCrossRef
50.
Romeo HE, Tio DL, Rahman SU, Chiappelli F, Taylor AN. The glossopharyngeal nerve as a novel pathway in immuneto-brain communication: relevance to neuroimmune surveillance of the oral cavity. J Neuroimmunol. 2001;115:91–100.PubMedCrossRef
51.
Schaefer ML, Böttger B, Silver WL, Finger TE. Trigeminal collaterals in the nasal epithelium and olfactory bulb: a potential route for direct modulation of olfactory information by trigeminal stimuli. J Comp Neurol. 2002;444:221–6.PubMedCrossRef
52.
Siddiqui TA, Lively S, Schlichter LC. Complex molecular and functional outcomes of single versus sequential cytokine stimulation of rat microglia. J Neuroinflamm. 2016;13:66.CrossRef
53.
Singhal G, Jaehne EJ, Corrigan F, Toben C, Baune BT. Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front Neurosci. 2014;8:315.PubMedPubMedCentralCrossRef
54.
Pereira L, Medina R, Baena M, Planas AM, Pozas E. IFN gamma regulates proliferation and neuronal differentiation by STAT1 in adult SVZ niche. Front Cell Neurosci. 2015;9:270.PubMedPubMedCentralCrossRef
55.
Turbic A, Leong SY, Turnley AM. Chemokines and inflammatory mediators interact to regulate adult murine neural precursor cell proliferation, survival and differentiation. PLoS ONE. 2011;6:e25406.PubMedPubMedCentralCrossRef
56.
Walter J, Honsek SD, Illes S, Wellen JM, Hartung HP, Rose CR, Dihné M. A new role for interferon gamma in neural stem/precursor cell dysregulation. Mol Neurodegener. 2011;6:18.PubMedPubMedCentralCrossRef
57.
Urata S, Maruyama J, Kishimoto-Urata M, Sattler RA, Cook R, Lin N, Yamasoba T, Makishima T, Paessler S. Regeneration profiles of olfactory epithelium after SARS-CoV-2 infection in golden syrian hamsters. ACS Chem Neurosci. 2021;12:589–95.PubMedCrossRef
58.
Jha MK, Jo M, Kim JH, Suk K. Microglia-astrocyte crosstalk: an intimate molecular conversation. Neuroscientist. 2019;25:227–40.PubMedCrossRef
Metadata
Title
Immunological status of the olfactory bulb in a murine model of Toll-like receptor 3-mediated upper respiratory tract inflammation
Authors
Ryoji Kagoya
Makiko Toma-Hirano
Junya Yamagishi
Naoyuki Matsumoto
Kenji Kondo
Ken Ito
Publication date
01-12-2022
Publisher
BioMed Central
Keyword
Cytokines
Published in
Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-022-02378-1

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