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


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.


TLR Innate immunity Osteoarthritis Pain DAMPs Alarmins 


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.


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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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