Regulation of pulmonary fibrosis by chemokine receptor CXCR3

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

Research output: Contribution to journalArticle

Abstract

CXC chemokine receptor3 (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.

Original languageEnglish (US)
Pages (from-to)291-299
Number of pages9
JournalJournal of Clinical Investigation
Volume114
Issue number2
DOIs
StatePublished - Jul 2004

ASJC Scopus subject areas

  • Medicine(all)

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    Jiang, D., Liang, J., Hodge, J., Lu, B., Zhu, Z., Yu, S., Fan, J., Gao, Y., Yin, Z., Homer, R., Gerard, C., & Noble, P. W. (2004). Regulation of pulmonary fibrosis by chemokine receptor CXCR3. Journal of Clinical Investigation, 114(2), 291-299. https://doi.org/10.1172/JCI16861