A potential mode of action for Anakinra in patients with arthrofibrosis following total knee arthroplasty

Abstract

Arthrofibrosis is a fibroproliferative disease characterised by excessive deposition of extracellular matrix components intra-articularly leading to pain and restricted range of movement. Although frequently observed following total knee arthroplasty (TKA) no therapeutic options exist. A pilot study demonstrated that intra-articular injection of Anakinra, an IL-1R antagonist, improved range of movement and pain in patients with arthrofibrosis however the mechanism of action is unknown. We hypothesise that IL-1α/β will drive an inflammatory phenotype in fibroblasts isolated from the knee, therefore identifying a potential mechanism of action for Anakinra in arthrofibrosis following TKA. Fibroblasts isolated from synovial membranes and infra-patellar fat pad of patients undergoing TKA express high levels of IL-1R1. Stimulation with IL-1α/β induced a pro-inflammatory phenotype characterised by increased secretion of GMCSF, IL-6 and IL-8. No significant difference in the inflammatory response was observed between fibroblasts isolated from synovial membrane or infra-patellar fat pad. IL-1α/β treatments induced a pro-inflammatory phenotype in fibroblasts from both synovial membrane and infra-patellar fat pad and therefore Anakinra can likely have an inhibitory effect on fibroblasts present in both tissues in vivo. It is also likely that fibroblast responses in the tissues are controlled by IL-1α/β availability and not their ability to respond to it.

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

“…10 , 11 , 12 , 13 We recently described how epithelial stress, via release of IL-1α, triggers the polarization of lung fibroblasts toward a proinflammatory phenotype characterized by their highly abundant secretion of IL-6, IL-8, chemokine (C-C motif) ligand (CCL) 2 (monocyte chemoattractant protein-1), and granulocyte-macrophage colony-stimulating factor. 14 , 15 Similar inflammatory cytokine release has also been described in hepatic stellate cells, 16 cardiac fibroblasts, 17 dermal fibroblasts, 18 and fibroblasts isolated from the knee, 19 suggesting the ability to adopt an immunomodulatory state may be a ubiquitous property of fibroblasts. Herein, we hypothesized that fibroblasts persisting within fibrotic microenvironments may be a source of stress-induced inflammatory exacerbations and pain.…”

“… 22 Furthermore, we now demonstrate that fibroblasts in the post-TKA joint express IL-1R1 ( Figure 1 A). IL-1α polarizes fibroblasts toward a proinflammatory state 19 and is elevated in both the post-TKA infrapatellar fat pad and synovial fluid ( Figure 1 B). Fibroblasts isolated from the infrapatellar fat pad and exposed to pg/mL levels of IL-1α underwent a dramatic induction of CCL2, IL-6, and IL-8, all being secreted at ng/mL levels.…”

“… 22 The fibrotic matrix of the TKA joint is also characterized by the persistence of high numbers of α-smooth muscle actin– and IL-1R1–positive fibroblasts. 19 , 35 Herein, we discovered that the fibrotic post-TKA knee is characterized by a chronic inflammatory signature and identify IL-1R1–positive fibroblasts as a potential source of proinflammatory mediators that promote monocyte recruitment and pain in the TKA joint. This occurs via a paracrine pathway in which soluble IL-1α stimulates NF-κB–dependent expression of CCL2.…”

“…Mesenchymal phenotype was confirmed, as previously described. 19 Fibroblasts were reanimated and used between P2 and P5 for all experiments in this study.…”

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

“…The markers investigated in this study fulfilled two inclusion criteria; (i) they had previously been found significantly elevated in SF in revision TKR patients 14 ; and (ii) they are well characterized as mediators of fibrosis, inflammation, and/or pain. 12,13,15 Specifically we were interested in proinflammatory and immune cell recruitment mediators, including the CCL family of chemokines. GM-CSF is produced by fibroblasts, promotes neutrophil and macrophage proliferation and maturation, and is upregulated immediately postoperatively in serum following TKA.…”