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.
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Research Article|
October 17 2014
CXCR4 dysfunction in non-alcoholic steatohepatitis in mice and patients
Hédia Boujedidi;
Hédia Boujedidi
1
*Univ Paris-Sud, Faculté de Médecine Paris-Sud, Kremlin-Bicêtre, France
†INSERM U996, Clamart, France
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Olivier Robert;
Olivier Robert
1
*Univ Paris-Sud, Faculté de Médecine Paris-Sud, Kremlin-Bicêtre, France
†INSERM U996, Clamart, France
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Alexandre Bignon;
Alexandre Bignon
*Univ Paris-Sud, Faculté de Médecine Paris-Sud, Kremlin-Bicêtre, France
†INSERM U996, Clamart, France
‡Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT), Clamart, France
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Anne-Marie Cassard-Doulcier;
Anne-Marie Cassard-Doulcier
*Univ Paris-Sud, Faculté de Médecine Paris-Sud, Kremlin-Bicêtre, France
†INSERM U996, Clamart, France
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Marie-Laure Renoud;
Marie-Laure Renoud
†INSERM U996, Clamart, France
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Hélène Gary-Gouy;
Hélène Gary-Gouy
†INSERM U996, Clamart, France
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Patrice Hemon;
Patrice Hemon
†INSERM U996, Clamart, France
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Hugo Tharinger;
Hugo Tharinger
†INSERM U996, Clamart, France
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Sophie Prévot;
Sophie Prévot
*Univ Paris-Sud, Faculté de Médecine Paris-Sud, Kremlin-Bicêtre, France
§AP-HP, Hôpital Antoine Béclère, Service d’Anatomie Pathologique, Clamart, France
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Françoise Bachelerie;
Françoise Bachelerie
*Univ Paris-Sud, Faculté de Médecine Paris-Sud, Kremlin-Bicêtre, France
†INSERM U996, Clamart, France
‡Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT), Clamart, France
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Sylvie Naveau;
Sylvie Naveau
*Univ Paris-Sud, Faculté de Médecine Paris-Sud, Kremlin-Bicêtre, France
†INSERM U996, Clamart, France
∥AP-HP, Hôpital Antoine Béclère, Service d’Hépato-Gastroentérologie, DHU Hepatinov, Clamart, France
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Dominique Emilie;
Dominique Emilie
2
*Univ Paris-Sud, Faculté de Médecine Paris-Sud, Kremlin-Bicêtre, France
†INSERM U996, Clamart, France
‡Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT), Clamart, France
¶AP-HP, Hôpital Antoine Béclère, Service de Microbiologie-Immunologie Biologique, Clamart, France
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Karl Balabanian;
Karl Balabanian
*Univ Paris-Sud, Faculté de Médecine Paris-Sud, Kremlin-Bicêtre, France
†INSERM U996, Clamart, France
‡Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT), Clamart, France
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Gabriel Perlemuter
*Univ Paris-Sud, Faculté de Médecine Paris-Sud, Kremlin-Bicêtre, France
†INSERM U996, Clamart, France
∥AP-HP, Hôpital Antoine Béclère, Service d’Hépato-Gastroentérologie, DHU Hepatinov, Clamart, France
Correspondence: Professor Gabriel Perlemuter (email [email protected]).
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Publisher: Portland Press Ltd
Received:
December 23 2013
Revision Received:
July 02 2014
Accepted:
July 30 2014
Accepted Manuscript online:
July 30 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2015 Biochemical Society
2015
Clin Sci (Lond) (2015) 128 (4): 257–267.
Article history
Received:
December 23 2013
Revision Received:
July 02 2014
Accepted:
July 30 2014
Accepted Manuscript online:
July 30 2014
Citation
Hédia Boujedidi, Olivier Robert, Alexandre Bignon, Anne-Marie Cassard-Doulcier, Marie-Laure Renoud, Hélène Gary-Gouy, Patrice Hemon, Hugo Tharinger, Sophie Prévot, Françoise Bachelerie, Sylvie Naveau, Dominique Emilie, Karl Balabanian, Gabriel Perlemuter; CXCR4 dysfunction in non-alcoholic steatohepatitis in mice and patients. Clin Sci (Lond) 1 February 2015; 128 (4): 257–267. doi: https://doi.org/10.1042/CS20130833
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