title: Decreased interstitial FOXP3(+) lymphocytes in usual interstitial pneumonia with discrepancy of CXCL12/CXCR4 axis.
abstract: Regulatory T cells (Treg) play a critical role in immune homeostasis and expansion of Treg is controlled by chemokine receptors. The chemokine CXCL12 and its G-protein-coupled receptor (CXCR4) are involved in the development of idiopathic pulmonary fibrosis (IPF), but the association of Treg with the CXCL12/CXCR4 axis has not been documented. The aim of this study is to determine the distribution and extent of CXCL12/CXCR4 expression in idiopathic type of pulmonary fibrosis, and the relation of Treg expansion in the interstitium of pulmonary fibrosis patients to CXCL12/CXCR4 expression. CXCL12 expression was examined by immunostaining and ELISA in tissue specimens from patients with usual interstitial pneumonia (UIP, n=15), patients with fibrotic non-specific interstitial pneumonia (f-NSIP, n=4), and controls (n=6). CXCR4 expression was examined by in situ hybridization and immunoblotting. Expression of CD45, CD3, CD20, transcription factor forkhead box P3 (FOXP3), and CD25 was assessed by immunostaining. Fibrosis was evaluated by determining the established fibrosis (EF) score. The CXCL12/CXCR4 axis was upregulated in UIP and f-NSIP, and CXCL12 derived from lung tissue attracted CXCR4(+) cells. CXCR4(+) cells showed a CD3(+) cell distribution pattern. The interstitial FOXP3(+)/CD3(+) and CD25(+)/CD3(+) cell ratios were lower in UIP than f-NSIP, but the CXCR4(+)/CD3(+) cell ratio was not different. The FOXP3(+)/CD3(+) cell ratio and EF score were inversely correlated. These findings suggest that the CXCL12/CXCR4 axis contributes to inflammation in UIP and f-NSIP by promoting the accumulation CXCR4(+) lymphocytes, and a decrease of Treg is correlated with the severity of fibrosis in UIP.
authors.affiliation: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. yasuos@med.gunma-u.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Shimizu
authors.forename: K
authors.initials: K
authors.lastname: Dobashi
authors.forename: K
authors.initials: K
authors.lastname: Endou
authors.forename: A
authors.initials: A
authors.lastname: Ono
authors.forename: N
authors.initials: N
authors.lastname: Yanagitani
authors.forename: M
authors.initials: M
authors.lastname: Utsugi
authors.forename: T
authors.initials: T
authors.lastname: Sano
authors.forename: T
authors.initials: T
authors.lastname: Ishizuka
authors.forename: K
authors.initials: K
authors.lastname: Shimizu
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Mori
mesh_terms: D000328:Adult; D000368:Aged; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000502:physiology*; D000080027:Cyclams; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011658:Pulmonary Fibrosis / Q000209:etiology; D019718:Receptors, CXCR4 / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor