title: CXCR4 dysfunction in non-alcoholic steatohepatitis in mice and patients.
abstract: Homing of inflammatory cells to the liver is key in the progression of non-alcoholic steatohepatitis (NASH). An abnormal response of CD4+ T-cells from obese mice to the chemotactic effect of CXCL12 has been reported but the mechanism involved in this process and relevance in patients are unknown. We aimed to explore the mechanism involved in the abnormal chemotaxis of CXC chemokine ligand 12 (CXCL12) in several mouse models of NASH and the relevance in the context of human non-alcoholic fatty liver disease (NAFLD). We assessed chemotactic responsiveness of CD4+ T-cells to CXCL12, the effect of AMD3100, a CXC chemokine receptor 4 (CXCR4) antagonist, in mice and lymphocytes from patients with NAFLD, and the affinity of CXCL12 for CXCR4. CXCL12-promoted migration of CD4+ T-cells from three different mouse models of NASH was increased and dependent of CXCR4. CD4+ T-cells from patients with NASH, but not from patients with pure steatosis, responded more strongly to the chemotactic effect of CXCL12, and this response was inhibited by AMD3100. Treatment with AMD3100 decreased the number of CD4+ T-cells to the liver in ob/ob mice. CXCL12 expression in the liver, CXCR4 and CXCR7 expression in CD4+ T-cells were not increased in three different mouse models of NASH. However, the affinity of CXCL12 for CXCR4 was increased in CD4+ T-cells of ob/ob mice. In conclusion, the CXCL12/CXCR4 pathway contributes in both mice and patients to the enhanced recruitment of CD4+ T-cells in NASH. An increased affinity of CXCL12 to CXCR4 rather than a higher expression of the chemokine or its receptors is involved in this process.
authors: Hédia
authors: H
authors: Boujedidi
authors: Olivier
authors: O
authors: Robert
authors: Alexandre
authors: A
authors: Bignon
authors: Anne-Marie
authors: AM
authors: Cassard-Doulcier
authors: †INSERM U996, Clamart, France.
authors: Marie-Laure
authors: ML
authors: Renoud
authors: †INSERM U996, Clamart, France.
authors: Hélène
authors: H
authors: Gary-Gouy
authors: †INSERM U996, Clamart, France.
authors: Patrice
authors: P
authors: Hemon
authors: †INSERM U996, Clamart, France.
authors: Hugo
authors: H
authors: Tharinger
authors: Sophie
authors: S
authors: Prévot
authors: Françoise
authors: F
authors: Bachelerie
authors: Sylvie
authors: S
authors: Naveau
authors: Dominique
authors: D
authors: Emilie
authors: Karl
authors: K
authors: Balabanian
authors: Gabriel
authors: G
authors: Perlemuter
mesh_terms: D000328:Adult; D000818:Animals; D001596:Benzylamines; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D000080027:Cyclams; D004195:Disease Models, Animal; D005260:Female; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D054387:Receptors, CXCR / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001596:Benzylamines; D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; C088327:plerixafor