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.
Abbreviation:
APC (antigen-presenting cell), REX3 (Reporting the Expression of CXCR3 ligands)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: January 25, 2023
Accepted:
November 18,
2022
Received in revised form:
November 14,
2022
Received:
February 10,
2022
accepted manuscript published online XXX; corrected proof published online XXXPublication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
