The sphingosine 1-phosphate receptor S1P2 triggers hepatic wound healing.
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 alpha-actin mRNA and lower induction of TIMP-1, TGF-beta1, 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
Valérie
V
INSERM U841, Institut Mondor de Recherche Biomédicale, Hôpital Henri Mondor, 94010 Créteil, France.
Teixeira-Clerc
Fatima
F
Li
Liying
L
Schippers
Marlies
M
de Wries
Willie
W
Julien
Boris
B
Tran-Van-Nhieu
Jeanne
J
Manin
Sylvie
S
Poelstra
Klaas
K
Chun
Jerold
J
Carpentier
Stéphane
S
Levade
Thierry
T
Mallat
Ariane
A
Lotersztajn
Sophie
S
D000208:Acute Disease; D000818:Animals; D000077214:Becaplermin; D002252:Carbon Tetrachloride Poisoning / Q000235:genetics / Q000473:pathology; D002455:Cell Division; D002478:Cells, Cultured / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000473:pathology; D004261:DNA Replication / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology*; D008246:Lysophospholipids / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032390:Myoblasts, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D009336:Necrosis; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis; D049349:Receptors, Lysosphingolipid / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D000081025:Sphingosine-1-Phosphate Receptors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D000099157:Sphingosine Kinase
D000077214:Becaplermin; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D010982:Platelet-Derived Growth Factor; D018809:Proliferating Cell Nuclear Antigen; D020574:Proto-Oncogene Proteins c-sis; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D000099157:Sphingosine Kinase; C501285:S1pr3 protein, mouse; C060506:sphingosine 1-phosphate