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Fibroblasts Promote Inflammation and Pain via IL-1α Induction of the Monocyte Chemoattractant Chemokine (C-C Motif) Ligand 2

Lookup NU author(s): Dr Hannah Paish, Dr Nicholas Kalson, Dr Graham SmithORCiD, Alicia Del Carpio Pons, Nicholas Smith, Dr Kasla Swist-Szulik, Michelle Bardgett, Professor David Deehan, Professor Derek MannORCiD, Dr Lee BorthwickORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 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.

Publication metadata

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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