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Regulation of pulmonary fibrosis by chemokine receptor CXCR3
Dianhua Jiang, … , Craig Gerard, Paul W. Noble
Dianhua Jiang, … , Craig Gerard, Paul W. Noble
Published July 15, 2004
Citation Information: J Clin Invest. 2004;114(2):291-299. https://doi.org/10.1172/JCI16861.
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Article Immunology

Regulation of pulmonary fibrosis by chemokine receptor CXCR3

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Abstract

CXC chemokine receptor 3 (CXCR3) is the receptor for the IFN-γ–inducible C-X-C chemokines MIG/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11. CXCR3 is expressed on activated immune cells and proliferating endothelial cells. The role of CXCR3 in fibroproliferation has not been investigated. We examined the role of CXCR3 in pulmonary injury and repair in vivo. CXCR3-deficient mice demonstrated increased mortality with progressive interstitial fibrosis relative to WT mice. Increased fibrosis occurred without increased inflammatory cell recruitment. CXCR3 deficiency resulted in both a reduced early burst of IFN-γ production and decreased expression of CXCL10 after lung injury. We identified a relative deficiency in lung NK cells in the unchallenged CXCR3-deficient lung and demonstrated production of IFN-γ by WT lung NK cells in vivo following lung injury. The fibrotic phenotype in the CXCR3-deficient mice was significantly reversed following administration of exogenous IFN-γ or restoration of endogenous IFN-γ production by adoptive transfer of WT lymph node and spleen cells. Finally, pretreatment of WT mice with IFN-γ–neutralizing Ab’s enhanced fibrosis following lung injury. These data demonstrate a nonredundant role for CXCR3 in limiting tissue fibroproliferation and suggest that this effect may be mediated, in part, by the innate production of IFN-γ following lung injury.

Authors

Dianhua Jiang, Jiurong Liang, Jennifer Hodge, Bao Lu, Zhou Zhu, Shuang Yu, Juan Fan, Yunfei Gao, Zhinan Yin, Robert Homer, Craig Gerard, Paul W. Noble

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Figure 1

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Increased mortality from progressive lung fibrosis in CXCR3–/– mice foll...
Increased mortality from progressive lung fibrosis in CXCR3–/– mice following bleomycin-induced lung injury. (A) CXCR3–/– mice and WT C57BL/6J control mice were treated intratracheally with bleomycin. By day 14, 53.4% of CXCR3–/– mice were dead, whereas only 13.4% mortality was seen in WT mice. (B) Lung sections of CXCR3–/– or WT mice 10, 14, and 21 days after bleomycin instillation were stained with trichrome and counterstained with hematoxylin. Magnification,×100. Seven mice in each group were examined, and similar results were observed. Note that WT mice showed typical bleomycin-induced lung injury, whereas CXCR3–/– mice exhibited dramatic collagen staining. (C) Lung fibrosis after trichrome staining was quantitated by a pathologist in a blinded manner. The fibrotic area is presented as a percentage. *P = 0.05. (D) Lung tissue from CXCR3–/– mice and WT controls 14 and 21 days after bleomycin treatment was collected and assayed for collagen content using a conventional hydroxyproline assay. This is representative of three similar experiments. **P < 0.05.

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