Regulation of pulmonary fibrosis by chemokine receptor CXCR3

Dianhua Jiang

Jiurong Liang

Jennifer Hodge

Bao Lu

Zhinan Yin+3 authors

^{Department of Medicine, Section of Pulmonary and Critical Care, Yale University School of Medicine, New Haven, Connecticut, USA.}^{Perlmutter Laboratory, Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.}^{Section of Rheumatology, Yale University School of Medicine, New Haven, Connecticut, USA.}

Address correspondence to: Paul W. Noble, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, TAC 441-D, New Haven, Connecticut 06520-8057, USA. Phone: (203) 785-3627; Fax: (203) 785-3826; E-mail: ude.elay@elbon.luap.

Received 2002 Sep 9; Accepted 2004 May 4.

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.

Abstract

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Acknowledgments

This work was supported by NIH grant HL-60539 (P.W. Noble) and a Veteran’s Administration Merit Review Grant (P.W. Noble).

Acknowledgments

Footnotes

See the related Commentary beginning on page 165.

Nonstandard abbreviations used: bronchoalveolar lavage (BAL); CXC chemokine receptor 3 (CXCR3); idiopathic interstitial pneumonia (IIP); idiopathic pulmonary fibrosis (IPF).

Conflict of interest: P. Noble is a paid consultant for Intermune Pharmaceuticals, who is developing IFN-γ1b for therapeutic use in patients with pulmonary fibrosis. R. Homer has received honoraria from Intermune Pharmaceuticals for lecturing at CME-sponsored programs on the pathology of idiopathic pulmonary fibrosis.

Footnotes

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