Current Otorhinolaryngology Reports

, Volume 6, Issue 2, pp 203–208 | Cite as

Monocytes, Macrophages, and Microglia and the Role of IL-1 in Autoimmune Inner Ear Disease (AIED)

  • Andrea Vambutas
  • Shresh Pathak
Otology (A Vambutas, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Otology


Purpose of Review

Autoimmune inner ear disease (AIED) is a rare disease of unknown etiology characterized by a sudden decline in hearing. Although AIED is initially responsive to corticosteroid therapy, this response is lost over time. We recently demonstrated in a small cohort of corticosteroid-resistant AIED patients that IL-1 was overexpressed in the plasma and that IL-1 antagonism led to hearing improvement and reduction in circulating IL-1. Autoinflammatory diseases, such as Muckle-Wells syndrome (MWS), are diseases of the innate immune system whose phenotype includes sensorineural hearing loss. Monocytes are the primary cells orchestrating the inflammatory response in this family of diseases, due to a gain-of-function mutation that causes excessive IL-1 release.

Recent Findings

We have observed that monocytes from AIED patients release excessive IL-1 and behave similarly to monocytes from Muckle-Wells patients, despite the lack of pathogenic mutations and other characteristic phenotypic manifestations. Unlike MWS, we have observed substantially greater hearing improvement with IL-1 antagonism than hearing improvement reported in MWS.


The role of monocytes, macrophages, and microglia and the cytokines they secrete are of critical importance in both understanding disease mechanism and identification of novel therapeutic targets to treat chronic inflammatory diseases of the cochlea such as AIED.


Interleukin-1b (IL-1β) Tumor necrosis factor (TNF)-α Monocytes Macrophages Microglia AIED 


Compliance with Ethical Standards

Patients with AIED were recruited from the practice of Dr. Vambutas under an IRB-approved study at Northwell Health System.

Conflict of Interest

Dr. Vambutas reports consulting for Sobi Pharmaceuticals, the patent has been abandoned.

Dr. Pathak has nothing to disclose.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Harris JP, Weisman MH, Derebery JM, Espeland MA, Gantz BJ, Gulya AJ, et al. Treatment of corticosteroid-responsive autoimmune inner ear disease with methotrexate: a randomized controlled trial. JAMA. 2003;290(14):1875–83. Scholar
  2. 2.
    Broughton SS, Meyerhoff WE, Cohen SB. Immune mediated inner ear disease: 10-year experience. Semin Arthritis Rheum. 2004;34(2):544–8. Scholar
  3. 3.
    Lorenz RR, Solares CA, Williams P, Sikora J, Pelfrey CM, Hughes GB, et al. Interferon-gamma production to inner ear antigens by T cells from patients with autoimmune sensorineural hearing loss. J Neuroimmunol. 2002;130(1–2):173–8. Scholar
  4. 4.
    Fujioka M, Kanzaki S, Okano HJ, Masuda M, Ogawa K, Okano H. Proinflammatory cytokines expression in noise-induced damaged cochlea. J Neurosci Res. 2006;83(4):575–83. Scholar
  5. 5.
    Greter M, Lelios I, Croxford AL. Microglia versus myeloid cell nomenclature during brain inflammation. Front Immunol. 2015;6:249.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bhave SA, Oesterle EC, Coltrera MD. Macrophage and microglia-like cells in the avian inner ear. J Comp Neurol. 1998;398(2):241–56.<241::AID-CNE6>3.0.CO;2-0.CrossRefPubMedGoogle Scholar
  7. 7.
    Fuentes-Santamaria V, et al. The role of glia in the peripheral and central auditory system following noise overexposure: contribution of TNF-alpha and IL-1beta to the pathogenesis of hearing loss. Front Neuroanat. 2017;11:9.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kwon MS, Seo YJ, Lee JK, Lee HK, Jung JS, Jang JE, et al. The repeated immobilization stress increases IL-1beta immunoreactivities in only neuron, but not astrocyte or microglia in hippocampal CA1 region, striatum and paraventricular nucleus. Neurosci Lett. 2008;430(3):258–63. Scholar
  9. 9.
    •• Nakanishi H, Kawashima Y, Kurima K, Chae JJ, Ross AM, Pinto-Patarroyo G, et al. NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy. Proc Natl Acad Sci U S A. 2017;114(37):E7766–75. Demonstrates cochlear macrophages can mediate local inflammation and release of IL-1β through activation of the NLRP3 inflammasome. Scholar
  10. 10.
    Harris JP. Immunology of the inner ear: response of the inner ear to antigen challenge. Otolaryngol Head Neck Surg. 1983;91(1):18–32. Scholar
  11. 11.
    Colotta F, Saccani S, Giri JG, Dower SK, Sims JE, Introna M, et al. Regulated expression and release of the IL-1 decoy receptor in human mononuclear phagocytes. J Immunol. 1996;156:2534–41.PubMedGoogle Scholar
  12. 12.
    Yang CR, Wang JH, Hsieh SL, Wang SM, Hsu TL, Lin WW. Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells. Cell Death Differ. 2004;11(Suppl 1):S97–107. Scholar
  13. 13.
    McNamee EN, Ryan KM, Kilroy D, Connor TJ. Noradrenaline induces IL-1ra and IL-1 type II receptor expression in primary glial cells and protects against IL-1beta-induced neurotoxicity. Eur J Pharmacol. 2010;626(2–3):219–28. Scholar
  14. 14.
    Vambutas A, DeVoti J, Goldofsky E, Gordon M, Lesser M, Bonagura V. Alternate splicing of interleukin-1 receptor type II (IL1R2) in vitro correlates with clinical glucocorticoid responsiveness in patients with AIED. PLoS One. 2009;4(4):e5293. Scholar
  15. 15.
    Pathak S, Goldofsky E, Vivas EX, Bonagura VR, Vambutas A. IL-1beta is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease. J Immunol. 2011;186(3):1870–9. Scholar
  16. 16.
    Shimamura M, Nakagami H, Osako MK, Kurinami H, Koriyama H, Zhengda P, et al. OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice. Proc Natl Acad Sci U S A. 2014;111(22):8191–6. Scholar
  17. 17.
    Kichev A, Eede P, Gressens P, Thornton C, Hagberg H. Implicating receptor activator of NF-kappaB (RANK)/RANK ligand signalling in microglial responses to toll-like receptor stimuli. Dev Neurosci. 2017;39(1–4):192–206. Scholar
  18. 18.
    Zehnder AF, Kristiansen AG, Adams JC, Merchant SN, McKenna MJ. Osteoprotegerin in the inner ear may inhibit bone remodeling in the otic capsule. Laryngoscope. 2005;115(1):172–7. Scholar
  19. 19.
    Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29(3):301–5. Scholar
  20. 20.
    Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004;20(3):319–25. Scholar
  21. 21.
    •• Vambutas A, Pathak S. AAO: autoimmune and autoinflammatory (disease) in otology: what is new in immune-mediated hearing loss. Laryngoscope Investig Otolaryngol. 2016;1(5):110–5. Provides an overview of autoimmune and autoinflammatory diseases in the context of immune-mediated hearing loss. Scholar
  22. 22.
    Kuemmerle-Deschner JB, Koitschev A, Tyrrell PN, Plontke SK, Deschner N, Hansmann S, et al. Early detection of sensorineural hearing loss in Muckle-Wells-syndrome. Pediatr Rheumatol Online J. 2015;13(1):43. Scholar
  23. 23.
    Gattorno M, Tassi S, Carta S, Delfino L, Ferlito F, Pelagatti MA, et al. Pattern of interleukin-1beta secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations. Arthritis Rheum. 2007;56(9):3138–48. Scholar
  24. 24.
    • Vambutas A, et al. Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease. J Clin Invest. 2014;124(9):4115–22. Demonstrates in a small cohort of corticosteroid-resistant AIED patients IL-1 blockade is able to improve hearing thresholds while reducing plasma IL-1β. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Monteleone M, Stow JL, Schroder K. Mechanisms of unconventional secretion of IL-1 family cytokines. Cytokine. 2015;74(2):213–8. Scholar
  26. 26.
    Svrakic M, Pathak S, Goldofsky E, Hoffman R, Chandrasekhar SS, Sperling N, et al. Diagnostic and prognostic utility of measuring tumor necrosis factor in the peripheral circulation of patients with immune-mediated sensorineural hearing loss. Arch Otolaryngol Head Neck Surg. 2012;138(11):1052–8. Scholar
  27. 27.
    Cohen S, Shoup A, Weisman MH, Harris J. Etanercept treatment for autoimmune inner ear disease: results of a pilot placebo-controlled study. Otol Neurotol. 2005;26(5):903–7. Scholar
  28. 28.
    Matteson EL, Choi HK, Poe DS, Wise C, Lowe VJ, McDonald TJ, et al. Etanercept therapy for immune-mediated cochleovestibular disorders: a multicenter, open-label, pilot study. Arthritis Rheum. 2005;53(3):337–42. Scholar
  29. 29.
    Van Wijk F, et al. Local perfusion of the tumor necrosis factor alpha blocker infliximab to the inner ear improves autoimmune neurosensory hearing loss. Audiol Neurootol. 2006;11(6):357–65. Scholar
  30. 30.
    Derebery MJ, Fisher LM, Voelker CCJ, Calzada A. An open label study to evaluate the safety and efficacy of intratympanic golimumab therapy in patients with autoimmune inner ear disease. Otol Neurotol. 2014;35(9):1515–21. Scholar
  31. 31.
    Angeli SI, Abi-Hachem RN, Vivero RJ, Telischi FT, Machado JJ. L-N-acetylcysteine treatment is associated with improved hearing outcome in sudden idiopathic sensorineural hearing loss. Acta Otolaryngol. 2012;132(4):369–76. Scholar
  32. 32.
    Pathak S, Stern C, Vambutas A. N-acetylcysteine attenuates tumor necrosis factor alpha levels in autoimmune inner ear disease patients. Immunol Res. 2015;63(1–3):236–45. Scholar
  33. 33.
    Vambutas A, Lesser M, Mullooly V, Pathak S, Zahtz G, Rosen L, et al. Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease. J Clin Invest. 2014;124(9):4115–22. Scholar
  34. 34.
    Suckfuell M, Lisowska G, Domka W, Kabacinska A, Morawski K, Bodlaj R, et al. Efficacy and safety of AM-111 in the treatment of acute sensorineural hearing loss: a double-blind, randomized, placebo-controlled phase II study. Otol Neurotol. 2014;35(8):1317–26. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.The Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.The Apelian Cochlear Implant Center, Department of OtolaryngologyNorthwell Health SystemNew Hyde ParkUSA
  3. 3.Department of OtolaryngologyDonald and Barbara Zucker School of Medicine at Hofstra-NorthwellHempsteadUSA
  4. 4.Department of Molecular MedicineDonald and Barbara Zucker School of Medicine at Hofstra NorthwellHempsteadUSA
  5. 5.Department of Otorhinolaryngology - Head & Neck Surgery, Montefiore Medical CenterAlbert Einstein College of MedicineBronxUSA

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