Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis

RESEARCH ARTICLE Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis Anna-Maria Hoffmann-Vold ID1,2☯*, Stephen Samuel Weigt3☯, Vyacheslav Palchevskiy3, Elizabeth Volkmann3, Rajan Saggar3, Ning Li4, Øyvind Midtvedt1, May Brit Lund2,5, Torhild Garen1, Michael C. Fishbein6, Abbas Ardehali7, David J. Ross3, Thor Ueland8, Pål Aukrust8,9,10, Joseph P. Lynch III3, Robert M. Elashoff4, Øyvind Molberg1,2, John A. Belperio3 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Hoffmann-Vold A-M, Weigt SS, Palchevskiy V, Volkmann E, Saggar R, Li N, et al. (2018) Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis. PLoS ONE 13(11): e0206545. https://doi. org/10.1371/journal.pone.0206545 Editor: Masataka Kuwana, Keio University, JAPAN Received: May 1, 2018 Accepted: October 15, 2018 Published: November 20, 2018 Copyright: © 2018 Hoffmann-Vold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: There are ethical and legal restrictions on sharing a de-identified data set imposed by the Health authorities and the local ethical committee since our data contain potentially identifying or sensitive patient information. Data are available from the Oslo University Hospital/ Institutional Data Access / Ethics Committee for researchers who meet the criteria for access to confidential data. The contact information for the ethical committee is: REK sør-øst, Postboks 1130, Blindern, 0318 Oslo, Norway. 1 Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway, 2 Institute of Clinical Medicine, University of Oslo, Rikshospitalet, Oslo, Norway, 3 Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America, 4 Department of Biomathematics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America, 5 Department of Pulmonary Disease, Oslo University Hospital, Rikshospitalet, Norway, 6 Department of Pathology, UCLA, Los Angeles, California, United States of America, 7 Department of Surgery, UCLA, Los Angeles, California, United States of America, 8 Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Norway, 9 K.G. Jebsen Inflammatory Research Center, University of Oslo, Norway, 10 Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway ☯ These authors contributed equally to this work. * Abstract Background Dysregulation 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. 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). 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. Results CX3CL1 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 PLOS ONE | https://doi.org/10.1371/journal.pone.0206545 November 20, 2018 1 / 15 CX3CL1 in systemic sclerosis associated interstitial lung disease Funding: This work was supported by the National Institutes of Health (R01 HL 112990-01, 5U01A1 113315-02, P01Hl108793-06) (JAB), the UngerVetlesen Foundation and the Norwegian Women’s Public Health Association and the Norwegian Rheumatology Foundation (AMHV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. with anti-Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH. Conclusion CX3CL1 is associated with progressive SSc-ILD but not SSc-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. Competing interests: The authors have declared that no competing interests exist. Introduction 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 [1–3]. 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, more specifically interstitial lung disease (ILD) and pulmonary hypertension (PH) [4–6]. Multiple studies have demonstrated that the risk of death in SSc patients with these pulmonary complications increases 2 to 7 times [5–6]. The risk for ILD and PH is evident in SSc patients with the limited cutaneous form of the disease (lcSSc), where skin involvement is only detectable in areas distal to elbows and knees, and in those with the diffuse cutaneous form (dcSSc), where thickening of the skin occurs both proximal and distal [1]. The presence of anti-centromere antibodies (ACA) has been associated with PH while anti-topoisomerase I antibodies (ATA) associate with ILD, but these antibodies have poor negative predictive value [1,7]. The clinical course of PH and ILD in SSc is highly variable ranging from slowly evolving cases that may respond to targeted therapy to more progressive forms that may result in right heart failure or pulmonary fibrosis with respiratory failure and death [7,8]. The pathological processes leading to SSc-PH and SSc-ILD are not well understood, but they most likely involve complex mechanisms driven by inappropriate immune activation and enhanced fibrogenesis in the lungs, but the molecules that drives these interacting processes are not fully understood and hamper targeted therapeutic intervention [2,9]. Thus, 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. CX3CL1 is the only member of (...truncated)