%0 Journal Article
%T Fibroblasts Promote Inflammation and Pain via IL-1汐 Induction of the Monocyte Chemoattractant Chemokine (C-C Motif) Ligand 2
%A Alicia del Carpio Pons
%A David J. Deehan
%A David J. Weir
%A Derek A. Mann
%A Graham R. Smith
%A Hannah L. Paish
%A Katarzyna Swist-Szulik
%A Michelle Bardgett
%A Nicholas S. Kalson
%A Nicholas Smith
%A Thomas E. Baldock
%J Archive of "The American Journal of Pathology".
%D 2018
%R 10.1016/j.ajpath.2017.11.007
%X 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-1汐. Fibroblasts isolated from the post-TKA fibrotic infrapatellar fat pad express the IL-1 receptor and on exposure to IL-1汐 polarize to a highly inflammatory state that enables them to stimulate the recruitment of monocytes. Blockade of fibroblast CCL2 or its transcriptional regulator NF-百B prevented IL-1汐每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-1汐每NF-百B每CCL2 signaling pathway, operating within scar-associated fibroblasts, may be therapeutically manipulated for alleviating inflammation and pain in fibrotic joints and other tissues
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842035/