IFNL3 genotype is associated with pulmonary fibrosis in patients with systemic sclerosis

Fibrosis across different organs and tissues is likely to share common pathophysiological mechanisms and pathways. Recently, a polymorphism (rs12979860) near the interferon lambda gene (IFNL3) was shown to be associated with fibrosis in liver across multiple disease etiologies. We determined whether this variant is a risk factor for pulmonary fibrosis (PF) and worsening cutaneous fibrosis in systemic sclerosis (SSc). Caucasian patients with SSc (n = 733) were genotyped to test for association with the presence of PF and worsening of skin fibrosis. Serum IFN-λ3 levels from 200 SSc cases were evaluated. An association of the IFNL3 polymorphism with PF was demonstrated (OR: 1.66 (95% CI: 1.142–2.416, p = 0.008). The IFNL3 variant was not a risk factor for worsening of skin fibrosis. Functionally, IFN-λ3 serum levels were higher among subjects with PF compared to those unaffected (P < 0.0001). In conclusion, IFNL3 serum levels and the genetic variant known to be associated with liver fibrosis are similarly linked to PF, but not to worsening of skin fibrosis in SSc. These data highlight both common fibrosis pathways operating between organs, as well as differential effects within the same disease.

An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3

Morphea, or localized scleroderma, is characterized by an inflammatory phase followed by cutaneous fibrosis, which may lead to disfigurement and/or disability. Previous work from our group showed that the CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in lesional skin of morphea patients. Here, we used an acute inflammatory and fibrotic bleomycin mouse model of morphea to examine the role of the CXCR3 chemokine axis in pathogenesis. We first characterized which cells produce the CXCR3 ligands in the skin using the Reporter of Expression of CXCR3 ligands mouse (REX3). We found that fibroblasts contribute the bulk of CXCL9 and CXCL10, whereas endothelial cells are key dual chemokine producers. Macrophages, which have high MFI of chemokine expression, upregulated CXCL9 production over time, fibroblasts CXCL10 production, and T cells dual chemokine expression. To determine whether bleomycin treatment could directly induce expression of these chemokines, we treated cultured REX3 mouse dermis monolayers in vitro with bleomycin or IFNγ with TNF and found that bleomycin could induce low amounts of CXCL9 directly in fibroblasts, whereas the cytokines were required for optimal CXCL9 and CXCL10 production. To determine whether these chemokines are mechanistically involved in pathogenesis, we induced fibrosis in CXCL9, CXCL10, or CXCR3 deficient mice and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9, but not CXCL10, to cultured mouse fibroblasts induces collagen 1a1 mRNA expression, indicating the chemokine itself can contribute to fibrosis. Taken together, our studies provide evidence that acute intradermal bleomycin administration in mice can model inflammatory morphea, and that CXCL9 and its receptor CXCR3 are mechanistically involved in pathogenesis.One Sentence SummaryCXCL9 drives acute morphea pathogenesis in mice.