Augmented concentrations of CX(3)CL1 are associated with interstitial lung disease in systemic sclerosis

BACKGROUND: Dysregulation of Fractalkine (CX(3)CL1) and its receptor CX(3)CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX(3)CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial. METHODS: We collected lung tissue at the time of lung transplantation at UCLA from SSc-ILD patients (n = 12) and healthy donors (n = 12); and serum samples from the prospective Oslo University Hospital SSc cohort (n = 292) and healthy donors (n = 100). CX(3)CL1 was measured by ELISA. Cellular sources of CX(3)CL1/CX(3)CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed. RESULTS: CX(3)CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX(3)CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX(3)CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX(3)CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX(3)CL1 correlated with anti-Topoisomerase-I-antibody and lung fibrosis. CX(3)CL1 was associated with ILD progression in multivariable regression analysis but not PH. CONCLUSION: CX(3)CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX(3)CR1/CX(3)CL1-biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD.