{
  "abstract": "Introduction Exposure to crystalline silica (SiO2), a recognized risk factor of SSc, occurs in several occupations from the construction and rock industries. Several national reports (France, Australia, UK) highlight that SiO2 is still a topical hazard. SSc patients with a history of SiO2 exposure generally present a more severe phenotype, although such results vary depending on the studied populations. Despite this recognized association, the pathogenesis of SiO2-related SSc is poorly understood and there is no SSc mouse model based on SiO2 exposure which fully replicates the key hallmark features of SSc (i.e. vasculopathy, fibrosis and autoimmunity). The objective of this study was to characterize the phenotype of SSc patients exposed to SiO2 as compared to unexposed patients and to replicate these characteristics in a mouse model to gain insights into the underlying pathogenesis.Material and Methods SiO2 exposure was assessed using a dedicated questionnaire in SSc patients consecutively included at Rennes university Hospital (France). In mice, male autoimmune prone 129/Sv mice were exposed to 4 subcutaneous injections of human recombinant topoisomerase 1 (rTOPO) with Freund’s complete adjuvant (CFA), two weeks apart. They also received two oropharyngeal instillations of SiO2 (DQ12, 3 mg, representative of a lifetime occupational exposure to SiO2) or NaCl at weeks 1 and 3. After 8 weeks, the mice were euthanized and blood was collected for quantification of antinuclear antibodies (indirect immunofluorescent assays adapted for mice), anti-TOPO antibodies (ELISA), skin and lung biopsies for histological analysis and mRNA levels.Results 100 SSc patients were consecutively included. and 16% had a specific high occupational exposure to SiO2. These patients were more frequently men (p<0.001), had diffuse cutaneous subset (p<0.002), extended ILD (p=0.031) and a more frequent positivity for anti-Topoisomerase antibody (p=0.021). In mice, Ashcroft score and molecular analysis of the lung and skin showed that, in the rTOPO/CFA model, SiO2 instillations exacerbate fibrosis (with increased COL1A2, TGFβ, FN1), matrix remodeling (with increased MMP9, TIMP1), inflammation (with increased IL6, TNFα, CXCL10) and NLRP3 inflammasome activation (with increased IL1β, NLRP3, CASP1) as compared to NaCl instillations, both in the lung (local effects) and in the skin (systemic effects of SiO2). The rTOPO/CFA induced ANA and anti-TOPO antibody production (p<0.01) and SiO2 tended to increase their levels.Conclusions SiO2 inhalation in SSc patients was associated with a more severe phenotype, including more severe skin disease. In rTOPO mice, SiO2 inhalation also had systemic effects with exacerbated lung and skin involvement.",
  "authors": [
    {
      "affiliations": [
        "Univ Rennes, INSERM, EHESP, IRSET UMR S 1085, Rennes, France"
      ],
      "name": "Salomé Patry"
    },
    {
      "affiliations": [
        "Univ Rennes, INSERM, EHESP, IRSET UMR S 1085, Rennes, France"
      ],
      "name": "Laura Morin"
    },
    {
      "affiliations": [
        "Univ Rennes, INSERM, EHESP, IRSET UMR S 1085, Rennes, France"
      ],
      "name": "Lelong Marie"
    },
    {
      "affiliations": [
        "Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET UMR S 1085, Rennes, France"
      ],
      "name": "Alice Ballerie"
    },
    {
      "affiliations": [
        "Univ Rennes, CHU Rennes, INSERM, UMR 1236, Etablissement Français du Sang Bretagne, Rennes, France"
      ],
      "name": "Erwan Dumontet"
    },
    {
      "affiliations": [
        "Université catholique de Louvain (UCLouvain), Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institute o, Brussels, Belgium"
      ],
      "name": "Francois Huaux"
    },
    {
      "affiliations": [
        "CNRS UMR 8211, Inserm U988, EHESS, Paris Cité University, CERMES3, Paris, France"
      ],
      "name": "Catherine Cavalin"
    },
    {
      "affiliations": [
        "Univ Rennes, INSERM, EHESP, IRSET UMR S 1085, Rennes, France"
      ],
      "name": "Valerie Lecureur"
    },
    {
      "affiliations": [
        "Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET UMR S 1085, Rennes, France"
      ],
      "name": "Alain Lescoat"
    }
  ],
  "title": "P.020 Crystalline silica as an aetiological factor of systemic sclerosis: from epidemiological data to mechanistic considerations in mouse models",
  "uid": "2ccd10b3-458b-5d21-a3da-1bcc56689408"
}