Abstract
BackgroundDysregulation of Fractalkine (CX3CL1) and its receptor CX3CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial.MethodsWe 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). CX3CL1 was measured by ELISA. Cellular sources of CX3CL1/CX3CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed.ResultsCX3CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX3CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX3CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX3CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX3CL1 correlated with anti-Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH.ConclusionCX3CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX3CR1/CX3CL1-biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD.
Highlights
Systemic sclerosis (SSc) is a connective tissue disease characterized by distinct serum autoantibodies, vascular remodelling and chronic inflammation that drives fibrotic processes in multiple organs [1,2,3]
CX3CL1 is associated with progressive SSc-interstitial lung disease (ILD) but not SSc-pulmonary hypertension (PH)
The CX3CR1/CX3CL1biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD
Summary
Systemic sclerosis (SSc) is a connective tissue disease characterized by distinct serum autoantibodies, vascular remodelling and chronic inflammation that drives fibrotic processes in multiple organs [1,2,3]. With the onset of therapeutic strategies against rapidly progressive renal vascular damage (scleroderma renal crisis), survival among patients with SSc is predominately influenced by the development of pulmonary manifestations, interstitial lung disease (ILD) and pulmonary hypertension (PH) [4,5,6]. Multiple studies have demonstrated that the risk of death in SSc patients with these pulmonary complications increases 2 to 7 times [5,6]. An understanding of the pathobiology involved in SSc-PH and SSc-ILD could potentially lead to novel pharmacological targets that may either reverse or prevent the progression of these SSc associated pulmonary complications. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial
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