CXCL9 Links Skin Inflammation and Fibrosis through CXCR3-Dependent Upregulation of Col1a1 in Fibroblasts

J Invest Dermatol. 2023 Jul;143(7):1138-1146.e12. doi: 10.1016/j.jid.2022.11.025. Epub 2023 Jan 25.


Morphea is characterized by initial inflammation followed by fibrosis of the skin and soft tissue. Despite its substantial morbidity, the pathogenesis of morphea is poorly studied. Previous work showed that CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in the sera and lesional skin of patients with morphea. We found that an early inflammatory subcutaneous bleomycin mouse model of dermal fibrosis mirrors the clinical, histological, and immune dysregulation observed in human morphea. We used this model to examine the role of the CXCR3 chemokine axis in the pathogenesis of cutaneous fibrosis. Using the REX3 (Reporting the Expression of CXCR3 ligands) mice, we characterized which cells produce CXCR3 ligands over time. We found that fibroblasts contribute the bulk of CXCL9-RFP and CXCL10-BFP by percentage, whereas macrophages produce high amounts on a per-cell basis. To determine whether these chemokines are mechanistically involved in pathogenesis, we treated Cxcl9-, Cxcl10-, or Cxcr3-deficient mice with bleomycin and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9 but not CXCL10 to cultured mouse fibroblasts induced Col1a1 mRNA expression, indicating that the chemokine itself contributes to fibrosis. Taken together, our studies provide evidence that CXCL9 and its receptor CXCR3 are functionally required for inflammatory fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bleomycin / toxicity
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / metabolism
  • Chemokine CXCL9 / genetics
  • Chemokine CXCL9 / metabolism
  • Dermatitis*
  • Fibroblasts / metabolism
  • Fibrosis
  • Humans
  • Inflammation
  • Ligands
  • Mice
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR3 / metabolism
  • Scleroderma, Localized*
  • Up-Regulation


  • Chemokine CXCL10
  • Ligands
  • Chemokine CXCL9
  • Bleomycin
  • Receptors, CXCR3
  • CXCL9 protein, human
  • CXCR3 protein, human