Distinct CDH11+ circulating fibroblasts and immune cells co-expressing chemokine receptors in chronic inflammatory arthritis patients

Abstract

The mechanisms underlying the progression of chronic inflammatory arthritis, affecting over 1% of adults, remain largely unclear. Using single-cell mass cytometry on peripheral blood of patients with active rheumatoid and psoriatic arthritis, we identified various cells co-expressing mesenchymal markers, including the homotypic adhesion molecule cadherin-11 (CDH11), and chemokine receptors. Circulating fibroblasts (podoplanin+CD45−CD3−CD19−CD4−CD8−CD56−CD66b−CD294−) co-expressing CDH11 and CCR7 were found exclusively in patients and not in paired bone marrow samples, suggesting their origin from inflamed joints. Increased fibrocytes (CD34+HLA-DR+CD45+CD3−CD19−CD4−CD8−CD56−CD66b−CD294−) co-expressing CDH11 and CCR7 were also found in patients, being more prevalent in bone marrow than blood, supporting their bone marrow origin. Among various leukocyte subsets, CDH11+CD90+neutrophils co-expressing CCR6 were markedly increased in patients. Paired measurements three months post-antirheumatic treatment revealed persistently increased circulating CDH11+fibroblasts, CDH11+fibrocytes and CDH11+CD90+CCR6+neutrophils, regardless of clinical responses. Moreover, CDH11+neutrophils were identified by confocal microscopy in close proximity to synovial fibroblasts in knee-surgery-obtained rheumatoid synovium. Combining our findings with previous data showing circulating pre-inflammatory mesenchymal cells to precede clinical arthritis flares, we suggest a drug-independent process orchestrated by chemokines that may contribute to ‘arthritis spreading’, wherein synovial fibroblasts and fibrocytes migrate into distant synovium, either alone or by forming complexes with CD90+CDH11+ neutrophils, through CDH11-mediated binding.