CXCL9 links skin inflammation and fibrosis via CXCR3-dependent upregulation of collagen 1a1 in fibroblasts

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 CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in the sera and lesional skin of morphea patients. 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 Reporter of Expression of CXCR3 ligands mouse (REX3), we characterized which cells produce CXCR3 ligands over time. We found that fibroblasts contribute the bulk of CXCL9 and CXCL10 by percent, 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 collagen 1a1 mRNA expression, indicating the chemokine itself contributes to fibrosis. Taken together, our studies provide evidence that CXCL9 and its receptor CXCR3 are functionally required for inflammatory fibrosis.

 

Comments：

In a mouse model of dermal fibrosis, the CXCR3 chemokine axis, particularly CXCL9 and its receptor, was found to be functionally required for inflammatory fibrosis and the development of fibrosis is dependent on CXCL9 and CXCR3, with fibroblasts being the main contributors of CXCL9 and CXCL10 production.

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