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Lookup NU author(s): Dr Hannah Paish, Dr Nicholas Kalson, Dr Graham Smith, Alicia Del Carpio Pons, Nicholas Smith, Dr Kasla Swist-Szulik, Michelle Bardgett, Professor David Deehan, Professor Derek Mann, Dr Lee Borthwick
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2018 American Society for Investigative Pathology Fibroblasts persist within fibrotic scar tissue and exhibit considerable phenotypic and functional plasticity. Herein, we hypothesized that scar-associated fibroblasts may be a source of stress-induced inflammatory exacerbations and pain. To test this idea, we used a human model of surgery-induced fibrosis, total knee arthroplasty (TKA). Using a combination of tissue protein expression profiling and bioinformatics, we discovered that many months after TKA, the fibrotic joint exists in a state of unresolved chronic inflammation. Moreover, the infrapatellar fat pad, a soft tissue that becomes highly fibrotic in the post-TKA joint, expresses multiple inflammatory mediators, including the monocyte chemoattractant, chemokine (C-C motif) ligand (CCL) 2, and the innate immune trigger, IL-1α. Fibroblasts isolated from the post-TKA fibrotic infrapatellar fat pad express the IL-1 receptor and on exposure to IL-1α polarize to a highly inflammatory state that enables them to stimulate the recruitment of monocytes. Blockade of fibroblast CCL2 or its transcriptional regulator NF-κB prevented IL-1α–induced monocyte recruitment. Clinical investigations discovered that levels of patient-reported pain in the post-TKA joint correlated with concentrations of CCL2 in the joint tissue, such that the chemokine is effectively a pain biomarker in the TKA patient. We propose that an IL-1α–NF-κB–CCL2 signaling pathway, operating within scar-associated fibroblasts, may be therapeutically manipulated for alleviating inflammation and pain in fibrotic joints and other tissues.
Author(s): Paish HL, Kalson NS, Smith GR, del Carpio Pons A, Baldock TE, Smith N, Swist-Szulik K, Weir DJ, Bardgett M, Deehan DJ, Mann DA, Borthwick LA
Publication type: Article
Publication status: Published
Journal: American Journal of Pathology
Year: 2018
Volume: 188
Issue: 3
Pages: 696-714
Print publication date: 01/03/2018
Online publication date: 15/12/2017
Acceptance date: 09/11/2017
Date deposited: 05/03/2018
ISSN (print): 0002-9440
ISSN (electronic): 1525-2191
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.ajpath.2017.11.007
DOI: 10.1016/j.ajpath.2017.11.007
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