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

摘要

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 profiting 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 alpha. Fibroblasts isolated from the post-TKA fibrotic infrapatellar fat pad express the IL-1 alpha receptor and on exposure to IL-1 alpha polarize to a highly inflammatory state that enables them to stimulate the recruitment of monocytes. Blockade of fibroblast CCL2 or its transcriptional regulator NF-kappa B prevented IL-1 alpha 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 alpha NF-kappa B CCL2 signaling pathway, operating within scar-associated fibroblasts, may be therapeutically manipulated for alleviating inflammation and pain in fibrotic joints and other tissues.