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The sphingosine 1-phosphate receptor S1P₂ triggers hepatic wound healing

Valérie Serriere-Lanneau^*,,1, Fatima Teixeira-Clerc^*,,1, Liying Li^*,, Marlies Schippers^*,||, Willie de Wries^*,||, Boris Julien^*,, Jeanne Tran-Van-Nhieu^*,,, Sylvie Manin^*,, Klaas Poelstra^||, Jerold Chun^¶, Stéphane Carpentier, Thierry Levade^,, Ariane Mallat^*,, and Sophie Lotersztajn^*,,,2

^* INSERM, U841, IMRB, Créteil, France;

Université Paris 12, Faculté de Médecine, Créteil, France;

AP-HP, Groupe hospitalier Henri Mondor-Albert Chenevier, Service d’Hépatologie et de Gastroentérologie, Créteil, France;

AP-HP, Groupe hospitalier Henri Mondor-Albert Chenevier, Département de Pathologie, Créteil, France;

^|| Department of Pharmacokinetics and Drug Delivery, University of Groningen, Groningen, Netherlands;

^¶ Department of Molecular Biology, Helen L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, La Jolla, California, USA;

INSERM, IFR31, U858, Toulouse, France; and

Université Toulouse III Paul Sabatier, IFR31, Toulouse, France

²Correspondence: INSERM U841, Institut Mondor de Recherche Biomédicale, Hôpital Henri Mondor, 94010 Créteil, France. E-mail: sophie.lotersztajn{at}creteil.inserm.fr

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid produced by sphingosine kinase (SphK1 and 2). We previously showed that S1P receptors (S1P₁, S1P₂, and S1P₃) are expressed in hepatic myofibroblasts (hMF), a population of cells that triggers matrix remodeling during liver injury. Here we investigated the function of these receptors in the wound healing response to acute liver injury elicited by carbon tetrachloride, a process that associates hepatocyte proliferation and matrix remodeling. Acute liver injury was associated with the induction of S1P₂, S1P₃, SphK1, and SphK2 mRNAs and increased SphK activity, with no change in S1P₁ expression. Necrosis, inflammation, and hepatocyte regeneration were similar in S1P₂^–/– and wild-type (WT) mice. However, compared with WT mice, S1P₂^–/– mice displayed reduced accumulation of hMF, as shown by lower induction of smooth muscle -actin mRNA and lower induction of TIMP-1, TGF-ß1, and PDGF-BB mRNAs, overall reflecting reduced activation of remodeling in response to liver injury. The wound healing response was similar in S1P₃^–/– and WT mice. In vitro, S1P enhanced proliferation of cultured WT hMF, and PDGF-BB further enhanced the mitogenic effect of S1P. In keeping with these findings, PDGF-BB up-regulated S1P₂ and SphK1 mRNAs, increased SphK activity, and S1P₂ induced PDGF-BB mRNA. These effects were blunted in S1P₂^–/– cells, and S1P₂^–/– hMF exhibited reduced mitogenic and comitogenic responses to S1P. These results unravel a novel major role of S1P₂ in the wound healing response to acute liver injury by a mechanism involving enhanced proliferation of hMF.—Serriere-Lanneau, V., Teixeira-Clerc, F., Li, L., Schippers, M., de Wries, W., Julien, B., Tran-Van-Nhieu, J., Manin, S., Poelstra, K., Chun, J., Carpentier, S., Levade, T., Mallat, A., Lotersztajn, S. The sphingosine 1-phosphate receptor S1P₂ triggers hepatic wound healing.

Key Words: liver • hepatic myofibroblasts

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