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.