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Seminars in Immunopathology

, Volume 41, Issue 5, pp 583–594 | Cite as

An emerging role for Toll-like receptors at the neuroimmune interface in osteoarthritis

  • Rachel E. Miller
  • Carla R. Scanzello
  • Anne-Marie MalfaitEmail author
Review

Abstract

Osteoarthritis (OA) is a chronic progressive, painful disease of synovial joints, characterized by cartilage degradation, subchondral bone remodeling, osteophyte formation, and synovitis. It is now widely appreciated that the innate immune system, and in particular Toll-like receptors (TLRs), contributes to pathological changes in OA joint tissues. Furthermore, it is now also increasingly recognized that TLR signaling plays a key role in initiating and maintaining pain. Here, we reviewed the literature of the past 5 years with a focus on how TLRs may contribute to joint damage and pain in OA. We discuss biological effects of specific damage-associated molecular patterns (DAMPs) which act as TLR ligands in vitro, including direct effects on pain-sensing neurons. We then discuss the phenotype of transgenic mice that target TLR pathways, and provide evidence for a complex balance between pro- and anti-inflammatory signaling pathways activated by OA DAMPs. Finally, we summarize clinical evidence implicating TLRs in OA pathogenesis, including polymorphisms and surrogate markers of disease activity. Our review of the literature led us to propose a model where multi-directional crosstalk between connective tissue cells (chondrocytes, fibroblasts), innate immune cells, and sensory neurons in the affected joint may promote OA pathology and pain.

Keywords

TLR Innate immunity Osteoarthritis Pain DAMPs Alarmins 

Notes

Funding information

REM is supported by the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (K01AR070328). AMM (R01AR064251 and R01AR060364) is supported by NIAMS. CRS is supported by the VA Rehabilitation Research and Development Service (RX001757), and funding from the University of Pennsylvania Perelman School of Medicine.

Compliance with ethical standards

Conflict of interest

R. E. Miller and C.R. Scanzello have no conflicts to declare. A.M. Malfait has received research funding from Galapagos N.V. and from GSK, and consulting fees from Eli-Lilly/Pfizer, EMD Serono, and Vizuri.

References

  1. 1.
    Collaborators GDaIIaP (2017) Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390(10100):1211–1259Google Scholar
  2. 2.
    Puig-Junoy J, Ruiz Zamora A (2015) Socio-economic costs of osteoarthritis: a systematic review of cost-of-illness studies. Semin Arthritis Rheum 44(5):531–541PubMedGoogle Scholar
  3. 3.
    Hawker GA, Croxford R, Bierman AS, Harvey PJ, Ravi B, Stanaitis I, Lipscombe LL (2014) All-cause mortality and serious cardiovascular events in people with hip and knee osteoarthritis: a population based cohort study. PLoS One 9(3):e91286PubMedPubMedCentralGoogle Scholar
  4. 4.
    Ravi B, Croxford R, Reichmann WM, Losina E, Katz JN, Hawker GA (2012) The changing demographics of total joint arthroplasty recipients in the United States and Ontario from 2001 to 2007. Best Pract Res Clin Rheumatol 26(5):637–647PubMedGoogle Scholar
  5. 5.
    Ackerman IN, Kemp JL, Crossley KM, Culvenor AG, Hinman RS (2017) Hip and knee osteoarthritis affects younger people, too. J Orthop Sports Phys Ther 47(2):67–79PubMedGoogle Scholar
  6. 6.
    Castagnini F, Sudanese A, Bordini B, Tassinari E, Stea S, Toni A (2017) Total knee replacement in young patients: survival and causes of revision in a registry population. J Arthroplast 32(11):3368–3372Google Scholar
  7. 7.
    Orlowsky EW, Kraus VB (2015) The role of innate immunity in osteoarthritis: when our first line of defense goes on the offensive. J Rheumatol 42(3):363–371PubMedPubMedCentralGoogle Scholar
  8. 8.
    Scanzello CR (2017) Role of low-grade inflammation in osteoarthritis. Curr Opin Rheumatol 29(1):79–85PubMedPubMedCentralGoogle Scholar
  9. 9.
    Syx D, Tran PB, Miller RE, Malfait AM (2018) Peripheral mechanisms contributing to osteoarthritis pain. Curr Rheumatol Rep 20(2):9PubMedPubMedCentralGoogle Scholar
  10. 10.
    Neogi T (2017) Structural correlates of pain in osteoarthritis. Clin Exp Rheumatol 35 Suppl 107(5):75–78PubMedGoogle Scholar
  11. 11.
    Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139(2):267–284PubMedPubMedCentralGoogle Scholar
  12. 12.
    Woller SA, Eddinger KA, Corr M, Yaksh TL (2018) An overview of pathways encoding nociception. Clin Exp Rheumatol 36(1):172PubMedGoogle Scholar
  13. 13.
    Matsuda M, Huh Y, Ji RR (2019) Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. J Anesth 33(1):131–139PubMedGoogle Scholar
  14. 14.
    Denk F, Bennett DL, McMahon SB (2017) Nerve growth factor and pain mechanisms. Annu Rev Neurosci 40:307–325PubMedGoogle Scholar
  15. 15.
    Pinho-Ribeiro FA, Verri WA Jr, Chiu IM (2017) Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol 38(1):5–19PubMedGoogle Scholar
  16. 16.
    Miller RE, Tran PB, Das R, Ghoreishi-Haack N, Ren D, Miller RJ, Malfait AM (2012) CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis. Proc Natl Acad Sci U S A 109(50):20602–20607PubMedPubMedCentralGoogle Scholar
  17. 17.
    Nefla M, Holzinger D, Berenbaum F, Jacques C (2016) The danger from within: alarmins in arthritis. Nat Rev Rheumatol 12(11):669–683PubMedGoogle Scholar
  18. 18.
    Lacagnina MJ, Watkins LR, Grace PM (2018) Toll-like receptors and their role in persistent pain. Pharmacol Ther 184:145–158PubMedGoogle Scholar
  19. 19.
    Kawasaki T, Kawai T (2014) Toll-like receptor signaling pathways. Front Immunol 5:461PubMedPubMedCentralGoogle Scholar
  20. 20.
    Sokolove J, Lepus CM (2013) Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Ther Adv Musculoskelet Dis 5(2):77–94PubMedPubMedCentralGoogle Scholar
  21. 21.
    van den Bosch MHJ (2019) Inflammation in osteoarthritis: is it time to dampen the alarm(in) in this debilitating disease? Clin Exp Immunol 195(2):153–166PubMedGoogle Scholar
  22. 22.
    Gomez R, Villalvilla A, Largo R, Gualillo O, Herrero-Beaumont G (2015) TLR4 signalling in osteoarthritis--finding targets for candidate DMOADs. Nat Rev Rheumatol 11(3):159–170PubMedGoogle Scholar
  23. 23.
    Rosenthal AK (2011) Crystals, inflammation, and osteoarthritis. Curr Opin Rheumatol 23(2):170–173PubMedPubMedCentralGoogle Scholar
  24. 24.
    Miller RE, Belmadani A, Ishihara S, Tran PB, Ren D, Miller RJ, Malfait AM (2015) Damage-associated molecular patterns generated in osteoarthritis directly excite murine nociceptive neurons through Toll-like receptor 4. Arthritis Rheumatol 67(11):2933–2943PubMedPubMedCentralGoogle Scholar
  25. 25.
    Wadachi R, Hargreaves KM (2006) Trigeminal nociceptors express TLR-4 and CD14: a mechanism for pain due to infection. J Dent Res 85(1):49–53PubMedPubMedCentralGoogle Scholar
  26. 26.
    Guerrero AT, Pinto LG, Cunha FQ, Ferreira SH, Alves-Filho JC, Verri WA Jr, Cunha TM (2016) Mechanisms underlying the hyperalgesic responses triggered by joint activation of TLR4. Pharmacol Rep 68(6):1293–1300PubMedGoogle Scholar
  27. 27.
    Tortorella MD, Malfait AM (2008) Will the real aggrecanase(s) step up: evaluating the criteria that define aggrecanase activity in osteoarthritis. Curr Pharm Biotechnol 9(1):16–23PubMedGoogle Scholar
  28. 28.
    Fosang AJ, Neame PJ, Hardingham TE, Murphy G, Hamilton JA (1991) Cleavage of cartilage proteoglycan between G1 and G2 domains by stromelysins. J Biol Chem 266(24):15579–15582PubMedGoogle Scholar
  29. 29.
    Lees S, Golub SB, Last K, Zeng W, Jackson DC, Sutton P, Fosang AJ (2015) Bioactivity in an aggrecan 32-mer fragment is mediated via Toll-like receptor 2. Arthritis Rheumatol 67(5):1240–1249PubMedGoogle Scholar
  30. 30.
    Little CB, Meeker CT, Golub SB, Lawlor KE, Farmer PJ, Smith SM, Fosang AJ (2007) Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair. J Clin Invest 117(6):1627–1636PubMedPubMedCentralGoogle Scholar
  31. 31.
    Miller RE, Ishihara S, Tran PB, Golub SB, Last K, Miller RJ, Fosang AJ, Malfait AM (2018) An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2. JCI Insight 3:6Google Scholar
  32. 32.
    Schaefer L, Babelova A, Kiss E, Hausser HJ, Baliova M, Krzyzankova M, Marsche G, Young MF, Mihalik D, Gotte M et al (2005) The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J Clin Invest 115(8):2223–2233PubMedPubMedCentralGoogle Scholar
  33. 33.
    Zeng-Brouwers J, Beckmann J, Nastase MV, Iozzo RV, Schaefer L (2014) De novo expression of circulating biglycan evokes an innate inflammatory tissue response via MyD88/TRIF pathways. Matrix Biol 35:132–142PubMedGoogle Scholar
  34. 34.
    Barreto G, Soininen A, Ylinen P, Sandelin J, Konttinen YT, Nordstrom DC, Eklund KK (2015) Soluble biglycan: a potential mediator of cartilage degradation in osteoarthritis. Arthritis Res Ther 17:379PubMedPubMedCentralGoogle Scholar
  35. 35.
    Avenoso A, D'Ascola A, Scuruchi M, Mandraffino G, Calatroni A, Saitta A, Campo S, Campo GM (2018) The proteoglycan biglycan mediates inflammatory response by activating TLR-4 in human chondrocytes: inhibition by specific siRNA and high polymerized Hyaluronan. Arch Biochem Biophys 640:75–82PubMedGoogle Scholar
  36. 36.
    Poluzzi C, Nastase MV, Zeng-Brouwers J, Roedig H, Hsieh LT, Michaelis JB, Buhl EM, Rezende F, Manavski Y, Bleich A et al (2019) Biglycan evokes autophagy in macrophages via a novel CD44/Toll-like receptor 4 signaling axis in ischemia/reperfusion injury. Kidney Int 95(3):540–562PubMedGoogle Scholar
  37. 37.
    Roedig H, Nastase MV, Wygrecka M, Schaefer L (2019) Breaking down chronic inflammatory diseases: the role of biglycan in promoting a switch between inflammation and autophagy. FEBS J 286:2965–2979PubMedGoogle Scholar
  38. 38.
    Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122(3):787–795PubMedPubMedCentralGoogle Scholar
  39. 39.
    Chockalingam PS, Glasson SS, Lohmander LS (2013) Tenascin-C levels in synovial fluid are elevated after injury to the human and canine joint and correlate with markers of inflammation and matrix degradation. Osteoarthr Cartil 21(2):339–345PubMedGoogle Scholar
  40. 40.
    Midwood K, Sacre S, Piccinini AM, Inglis J, Trebaul A, Chan E, Drexler S, Sofat N, Kashiwagi M, Orend G, Brennan F, Foxwell B (2009) Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med 15(7):774–780PubMedGoogle Scholar
  41. 41.
    Zuliani-Alvarez L, Marzeda AM, Deligne C, Schwenzer A, McCann FE, Marsden BD, Piccinini AM, Midwood KS (2017) Mapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers. Nat Commun 8(1):1595PubMedPubMedCentralGoogle Scholar
  42. 42.
    Okamura N, Hasegawa M, Nakoshi Y, Iino T, Sudo A, Imanaka-Yoshida K, Yoshida T, Uchida A (2010) Deficiency of tenascin-C delays articular cartilage repair in mice. Osteoarthr Cartil 18(6):839–848PubMedGoogle Scholar
  43. 43.
    Matsui Y, Hasegawa M, Iino T, Imanaka-Yoshida K, Yoshida T, Sudo A (2018) Tenascin-C prevents articular cartilage degeneration in murine osteoarthritis models. Cartilage 9(1):80–88PubMedGoogle Scholar
  44. 44.
    Kato J, Agalave NM, Svensson CI (2016) Pattern recognition receptors in chronic pain: mechanisms and therapeutic implications. Eur J Pharmacol 788:261–273PubMedGoogle Scholar
  45. 45.
    Liu XJ, Liu T, Chen G, Wang B, Yu XL, Yin C, Ji RR (2016) TLR signaling adaptor protein MyD88 in primary sensory neurons contributes to persistent inflammatory and neuropathic pain and neuroinflammation. Sci Rep 6:28188PubMedPubMedCentralGoogle Scholar
  46. 46.
    Nasi S, Ea HK, Chobaz V, van Lent P, Liote F, So A, Busso N (2014) Dispensable role of myeloid differentiation primary response gene 88 (MyD88) and MyD88-dependent toll-like receptors (TLRs) in a murine model of osteoarthritis. Joint Bone Spine 81(4):320–324PubMedGoogle Scholar
  47. 47.
    Stokes JA, Cheung J, Eddinger K, Corr M, Yaksh TL (2013) Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice. J Neuroinflammation 10:148PubMedPubMedCentralGoogle Scholar
  48. 48.
    Christianson CA, Dumlao DS, Stokes JA, Dennis EA, Svensson CI, Corr M, Yaksh TL (2011) Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis. Pain 152(12):2881–2891PubMedPubMedCentralGoogle Scholar
  49. 49.
    Sambamurthy N, Zhou C, Nguyen V, Smalley R, Hankenson KD, Dodge GR, Scanzello CR (2018) Deficiency of the pattern-recognition receptor CD14 protects against joint pathology and functional decline in a murine model of osteoarthritis. PLoS One 13(11):e0206217PubMedPubMedCentralGoogle Scholar
  50. 50.
    Inglis JJ, McNamee KE, Chia SL, Essex D, Feldmann M, Williams RO, Hunt SP, Vincent T (2008) Regulation of pain sensitivity in experimental osteoarthritis by the endogenous peripheral opioid system. Arthritis Rheum 58(10):3110–3119PubMedGoogle Scholar
  51. 51.
    Blom AB, van Lent PL, Abdollahi-Roodsaz S, van der Kraan PM, van den Berg WB: Toll like receptor-2 prevents cartilage damage in osteoarthritis models that display synovial activation. In: Orthopaedic Research Society annual meeting. San Francisco; 2012Google Scholar
  52. 52.
    Schelbergen RF, de Munter W, van den Bosch MH, Lafeber FP, Sloetjes A, Vogl T, Roth J, van den Berg WB, van der Kraan PM, Blom AB et al (2016) Alarmins S100A8/S100A9 aggravate osteophyte formation in experimental osteoarthritis and predict osteophyte progression in early human symptomatic osteoarthritis. Ann Rheum Dis 75(1):218–225PubMedGoogle Scholar
  53. 53.
    van Lent PL, Blom AB, Schelbergen RF, Sloetjes A, Lafeber FP, Lems WF, Cats H, Vogl T, Roth J, van den Berg WB (2012) Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis. Arthritis Rheum 64(5):1466–1476PubMedGoogle Scholar
  54. 54.
    Schelbergen RF, Geven EJ, van den Bosch MH, Eriksson H, Leanderson T, Vogl T, Roth J, van de Loo FA, Koenders MI, van der Kraan PM et al (2015) Prophylactic treatment with S100A9 inhibitor paquinimod reduces pathology in experimental collagenase-induced osteoarthritis. Ann Rheum Dis 74(12):2254–2258PubMedGoogle Scholar
  55. 55.
    Liu-Bryan R, Pritzker K, Firestein GS, Terkeltaub R (2005) TLR2 signaling in chondrocytes drives calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation. J Immunol 174(8):5016–5023PubMedGoogle Scholar
  56. 56.
    Su SL, Tsai CD, Lee CH, Salter DM, Lee HS (2005) Expression and regulation of Toll-like receptor 2 by IL-1beta and fibronectin fragments in human articular chondrocytes. Osteoarthr Cartil 13(10):879–886PubMedGoogle Scholar
  57. 57.
    Kim HA, Cho ML, Choi HY, Yoon CS, Jhun JY, Oh HJ, Kim HY (2006) The catabolic pathway mediated by Toll-like receptors in human osteoarthritic chondrocytes. Arthritis Rheum 54(7):2152–2163PubMedGoogle Scholar
  58. 58.
    Hwang HS, Park SJ, Cheon EJ, Lee MH, Kim HA (2015) Fibronectin fragment-induced expression of matrix metalloproteinases is mediated by MyD88-dependent TLR-2 signaling pathway in human chondrocytes. Arthritis Res Ther 17:320PubMedPubMedCentralGoogle Scholar
  59. 59.
    Zhang Q, Hui W, Litherland GJ, Barter MJ, Davidson R, Darrah C, Donell ST, Clark IM, Cawston TE, Robinson JH, Rowan AD, Young DA (2008) Differential Toll-like receptor-dependent collagenase expression in chondrocytes. Ann Rheum Dis 67(11):1633–1641PubMedGoogle Scholar
  60. 60.
    Sillat T, Barreto G, Clarijs P, Soininen A, Ainola M, Pajarinen J, Korhonen M, Konttinen YT, Sakalyte R, Hukkanen M, Ylinen P, Nordström DCE (2013) Toll-like receptors in human chondrocytes and osteoarthritic cartilage. Acta Orthop 84(6):585–592PubMedPubMedCentralGoogle Scholar
  61. 61.
    Barreto G, Sandelin J, Salem A, Nordstrom DC, Waris E (2017) Toll-like receptors and their soluble forms differ in the knee and thumb basal osteoarthritic joints. Acta Orthop 88(3):326–333PubMedPubMedCentralGoogle Scholar
  62. 62.
    Su SL, Yang HY, Lee CH, Huang GS, Salter DM, Lee HS (2012) The (-1486T/C) promoter polymorphism of the TLR-9 gene is associated with end-stage knee osteoarthritis in a Chinese population. J Orthop Res 30(1):9–14PubMedGoogle Scholar
  63. 63.
    Balbaloglu O, Sabah Ozcan S, Korkmaz M, Yilmaz N (2017) Promoter polymorphism (T-1486C) of TLR-9 gene is associated with knee osteoarthritis in a Turkish population. J Orthop Res 35(11):2484–2489PubMedGoogle Scholar
  64. 64.
    Yang HY, Lee HS, Lee CH, Fang WH, Chen HC, Salter DM, Su SL (2013) Association of a functional polymorphism in the promoter region of TLR-3 with osteoarthritis: a two-stage case-control study. J Orthop Res 31(5):680–685PubMedGoogle Scholar
  65. 65.
    Li C, Chen K, Kang H, Yan Y, Liu K, Guo C, Qi J, Yang K, Wang F, Guo L, He C, Deng L (2017) Double-stranded RNA released from damaged articular chondrocytes promotes cartilage degeneration via Toll-like receptor 3-interleukin-33 pathway. Cell Death Dis 8(11):e3165PubMedPubMedCentralGoogle Scholar
  66. 66.
    Huang ZY, Stabler T, Pei FX, Kraus VB (2016) Both systemic and local lipopolysaccharide (LPS) burden are associated with knee OA severity and inflammation. Osteoarthr Cartil 24(10):1769–1775PubMedPubMedCentralGoogle Scholar
  67. 67.
    Huang Z, Kraus VB (2016) Does lipopolysaccharide-mediated inflammation have a role in OA? Nat Rev Rheumatol 12(2):123–129PubMedGoogle Scholar
  68. 68.
    Kalaitzoglou E, Lopes EBP, Fu Y, Herron JC, Flaming JM, Donovan EL, Hu Y, Filiberti A, Griffin TM, Humphrey MB (2019) TLR4 promotes and DAP12 limits obesity-induced osteoarthritis in aged female mice. JBMR Plus 3(4):e10079PubMedGoogle Scholar
  69. 69.
    Guss JD, Ziemian SN, Luna M, Sandoval TN, Holyoak DT, Guisado GG, Roubert S, Callahan RL, Brito IL, van der Meulen MCH, Goldring SR, Hernandez CJ (2019) The effects of metabolic syndrome, obesity, and the gut microbiome on load-induced osteoarthritis. Osteoarthr Cartil 27(1):129–139PubMedGoogle Scholar
  70. 70.
    Lloyd-Jones KL, Kelly MM, Kubes P (2008) Varying importance of soluble and membrane CD14 in endothelial detection of lipopolysaccharide. J Immunol 181(2):1446–1453PubMedGoogle Scholar
  71. 71.
    Nair A, Kanda V, Bush-Joseph C, Verma N, Chubinskaya S, Mikecz K, Glant TT, Malfait AM, Crow MK, Spear GT, Finnegan A, Scanzello CR (2012) Synovial fluid from patients with early osteoarthritis modulates fibroblast-like synoviocyte responses to toll-like receptor 4 and toll-like receptor 2 ligands via soluble CD14. Arthritis Rheum 64(7):2268–2277PubMedPubMedCentralGoogle Scholar
  72. 72.
    Daghestani HN, Pieper CF, Kraus VB (2015) Soluble macrophage biomarkers indicate inflammatory phenotypes in patients with knee osteoarthritis. Arthritis Rheumatol 67(4):956–965PubMedPubMedCentralGoogle Scholar
  73. 73.
    Huang ZY, Perry E, Huebner JL, Katz B, Li YJ, Kraus VB (2018) Biomarkers of inflammation - LBP and TLR- predict progression of knee osteoarthritis in the DOXY clinical trial. Osteoarthr Cartil 26(12):1658–1665PubMedGoogle Scholar
  74. 74.
    Brandt KD, Mazzuca SA, Katz BP, Lane KA, Buckwalter KA, Yocum DE, Wolfe F, Schnitzer TJ, Moreland LW, Manzi S, Bradley JD, Sharma L, Oddis CV, Hugenberg ST, Heck LW (2005) Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum 52(7):2015–2025PubMedGoogle Scholar
  75. 75.
    Krock E, Currie JB, Weber MH, Ouellet JA, Stone LS, Rosenzweig DH, Haglund L (2016) Nerve growth factor is regulated by Toll-like receptor 2 in human intervertebral discs. J Biol Chem 291(7):3541–3551PubMedGoogle Scholar
  76. 76.
    Minnone G, De Benedetti F, Bracci-Laudiero L (2017) NGF and its receptors in the regulation of inflammatory response. Int J Mol Sci 18(5)PubMedCentralGoogle Scholar
  77. 77.
    Miller RE, Block JA, Malfait AM (2018) What is new in pain modification in osteoarthritis? Rheumatology (Oxford) 57(suppl_4):iv99–iv107Google Scholar
  78. 78.
    Baliu-Pique M, Jusek G, Holzmann B (2014) Neuroimmunological communication via CGRP promotes the development of a regulatory phenotype in TLR4-stimulated macrophages. Eur J Immunol 44(12):3708–3716PubMedGoogle Scholar
  79. 79.
    Gao W, Xiong Y, Li Q, Yang H (2017) Inhibition of Toll-like receptor signaling as a promising therapy for inflammatory diseases: a journey from molecular to nano therapeutics. Front Physiol 8:508PubMedPubMedCentralGoogle Scholar
  80. 80.
    Monnet E, Lapeyre G, Poelgeest EV, Jacqmin P, Graaf K, Reijers J, Moerland M, Burggraaf J, Min C (2017) Evidence of NI-0101 pharmacological activity, an anti-TLR4 antibody, in a randomized phase I dose escalation study in healthy volunteers receiving LPS. Clin Pharmacol Ther 101(2):200–208PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Rheumatology, Department of Internal MedicineRush University Medical CenterChicagoUSA
  2. 2.Section of Rheumatology and Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Veterans Affairs Medical Center & Division of RheumatologyUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA

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