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

Abstract

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.

Chronic, Active Inflammation in Patients With Failed Total Knee Replacements Undergoing Revision Surgery

“…Inflammation, fibrosis, and pain are dependent on immune cell recruitment and activation. We have previously found infiltration of CD68 + monocytes into fibrotic tissue . Therefore, we first examined GM‐CSF (increased ~threefold in SF of revision versus primary knees), IL‐5 (increased sixfold), IL‐8 (increased 39‐fold), and IL‐10 (increased twofold).…”

“…Data presented in this report suggest that the levels of key biologically active pro‐inflammatory mediators are locally elevated at time of revision surgery many years after the initial procedure in failed TKAs. The painful, fibrotic post‐TKA joint acquires a state of unresolved inflammation with a signature resembling that of a chronic allergic reaction . Markers with this temporal regulation include those involved in matrix formation (VEGF, Flt‐1) and the inflammatory cytokines GM‐CSF, IL‐5 and IL‐8, and cell recruitment chemokines CCL2, CCL3 and CCL4.…”

“…IL‐10 has been demonstrated to drive lung fibrosis when overexpressed, and this process is dependent on CCL2 signaling and is elevated in serum following knee surgery . CCL2 levels correlate positively with patient's pain levels following primary TKA, suggesting a role for CCL2 in pain pathogenesis, and recruitment of monocytes by knee fibroblasts in vitro is dependent on CCL2 signaling . CCL3 and CCL4 are elevated immediately following knee surgery and CCL13 is a key mediator of immune cell recruitment in chronic inflammation.…”

“…We and others have previously shown that the post‐TKA joint is associated with the persistence of myofibroblasts and extensive fibrotic remodeling . More recently, we have investigated the expression of 39 soluble inflammatory proteins in SF, fat pad (FP), and synovial membrane (SM) from patients undergoing either primary or revision surgery . There was elevated expression of a significant number of these markers in each anatomical location: n = 26/39 markers in SF, n = 22/39 in infrapatellar FP and n = 10/39 in SM in revision versus primary knees.…”

Increased symptoms of stiffness 1 year after total knee arthroplasty are associated with a worse functional outcome and lower rate of patient satisfaction

“…Approximated five percent of patients suffer stiffness as a significant complication after their TKA [6], and some require manipulation under anaesthesia [22] or revision surgery because of persistent stiffness [18]. Stiffness after knee arthroplasty may have a genetic component and epidemiological studies have found chromosomal changes in those reporting such symptoms [14], with an increased understanding of the biological basis for such a host response [16]. This is leading to a greater awareness that stiffness is potentially avoidable both from a mechanical and biological perspective [6].…”