TY - JOUR
T1 - CXCL9 Links Skin Inflammation and Fibrosis through CXCR3-Dependent Upregulation of Col1a1 in Fibroblasts
AU - Richmond, Jillian M.
AU - Patel, Dhrumil
AU - Watanabe, Tomoya
AU - Chen, Henry W.
AU - Martyanov, Viktor
AU - Werner, Giffin
AU - Garg, Madhuri
AU - Haddadi, Nazgol Sadat
AU - Refat, Maggi Ahmed
AU - Mahmoud, Bassel H.
AU - Wong, Lance D.
AU - Dresser, Karen
AU - Deng, April
AU - Zhu, Jane L.
AU - McAlpine, William
AU - Hosler, Gregory A.
AU - Feghali-Bostwick, Carol A.
AU - Whitfield, Michael L.
AU - Harris, John E.
AU - Torok, Kathryn S.
AU - Jacobe, Heidi T.
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/7
Y1 - 2023/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jid.2022.11.025
DO - 10.1016/j.jid.2022.11.025
M3 - Article
C2 - 36708947
AN - SCOPUS:85150854570
SN - 0022-202X
VL - 143
SP - 1138-1146.e12
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 7
ER -