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

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.