Regulation of pulmonary fibrosis by chemokine receptor CXCR3.
CXC chemokine receptor 3 (CXCR3) is the receptor for the IFN-gamma-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-gamma 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-gamma 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-gamma or restoration of endogenous IFN-gamma production by adoptive transfer of WT lymph node and spleen cells. Finally, pretreatment of WT mice with IFN-gamma-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-gamma following lung injury.
Jiang
Dianhua
D
Department of Medicine, Section of Pulmonary and Critical Care, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.
Liang
Jiurong
J
Hodge
Jennifer
J
Lu
Bao
B
Zhu
Zhou
Z
Yu
Shuang
S
Fan
Juan
J
Gao
Yunfei
Y
Yin
Zhinan
Z
Homer
Robert
R
Gerard
Craig
C
Noble
Paul W
PW
D019264:Adoptive Transfer; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D018893:Bronchoalveolar Lavage; D007371:Interferon-gamma / Q000008:administration & dosage / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology
D000903:Antibiotics, Antineoplastic; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D001761:Bleomycin; D007371:Interferon-gamma