PMID- 24917887
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20140611
LR  - 20211021
IS  - 1755-1536 (Print)
IS  - 1755-1536 (Electronic)
IS  - 1755-1536 (Linking)
VI  - 7
DP  - 2014
TI  - Anaphylatoxin C5a modulates hepatic stellate cell migration.
PG  - 9
LID - 10.1186/1755-1536-7-9 [doi]
AB  - BACKGROUND: C5a and its cognate receptor, C5a receptor (C5aR), key elements of 
      complement, are critical modulators of liver immunity and fibrosis. However, the 
      molecular mechanism for the cross talk between complement and liver fibrosis is 
      not well understood. C5a is a potent chemokine regulating migration of cells in 
      the innate immune system. Since activation and migration of hepatic stellate 
      cells (HSC) are hallmarks of liver fibrosis, we hypothesized that C5a contributes 
      to fibrosis by regulating HSC activation and/or migration. RESULTS: Primary 
      cultures of mouse HSC increased expression of alpha smooth muscle actin (alpha-SMA) 
      and collagen 1A (Col1A1) mRNA in response to activation on plastic. Expression of 
      mRNA for C5aR, but not C5L2, a second C5a receptor that acts as a negative 
      regulator, increased in parallel with markers of HSC activation in culture. 
      Increased expression of C5aR on activated HSC was confirmed by 
      immunocytochemistry. Cell surface expression of C5aR was also detected by flow 
      cytometry on activated HSC isolated from mice expressing GFP under the control of 
      the collagen promoter after exposure to chronic carbon tetrachloride. To 
      understand the functional significance of C5aR expression in HSC, we next 
      investigated whether C5a influenced HSC activation and/or migration. Challenge of 
      HSC with C5a during culture had no effect on expression of alpha-SMA and Col1A1, 
      suggesting that C5a did not influence HSC activation. Another important 
      characteristic of HSC is their migratory capacity; migration of HSC in response 
      to platelet derived growth factor (PDGF) and monocyte chemoattractant protein-1 
      (MCP-1) has been well characterized. Challenge of HSC with C5a enhanced HSC 
      migration almost as efficiently as PDGF in a two-dimensional wound healing and 
      Boyden chamber migration assays. C5a also stimulated expression of MCP-1. 
      C5a-induced cell migration was slowed, but not completely inhibited, in presence 
      of 227016, a MCP-1 receptor antagonist, suggesting C5a-induced migration occurs 
      via both MCP-1-dependent and -independent mechanisms. CONCLUSIONS: These data 
      reveal that C5a regulates migration of HSC and suggest a novel mechanism by which 
      complement contributes to hepatic fibrosis. C5a and its receptors are therefore 
      potential therapeutic targets for the prevention and/or treatment of liver 
      fibrosis.
FAU - Das, Dola
AU  - Das D
AD  - Center for Liver Disease Research, Department of Pathobiology, Lerner Research 
      Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
FAU - Barnes, Mark A
AU  - Barnes MA
AD  - Center for Liver Disease Research, Department of Pathobiology, Lerner Research 
      Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA ; Department of 
      Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
FAU - Nagy, Laura E
AU  - Nagy LE
AD  - Center for Liver Disease Research, Department of Pathobiology, Lerner Research 
      Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA ; Department of 
      Gastroenterology, Lerner Research Institute, Cleveland Clinic Foundation, 
      Cleveland, Ohio, USA ; Department of Molecular Medicine, Case Western Reserve 
      University, Cleveland, Ohio, USA.
LA  - eng
GR  - UL1 TR000439/TR/NCATS NIH HHS/United States
PT  - Journal Article
DEP - 20140530
PL  - England
TA  - Fibrogenesis Tissue Repair
JT  - Fibrogenesis & tissue repair
JID - 101464642
PMC - PMC4050393
OTO - NOTNLM
OT  - Chemotaxis
OT  - Complement
OT  - Fibrosis
OT  - Wound healing
EDAT- 2014/06/12 06:00
MHDA- 2014/06/12 06:01
PMCR- 2014/05/30
CRDT- 2014/06/12 06:00
PHST- 2014/01/14 00:00 [received]
PHST- 2014/04/22 00:00 [accepted]
PHST- 2014/06/12 06:00 [entrez]
PHST- 2014/06/12 06:00 [pubmed]
PHST- 2014/06/12 06:01 [medline]
PHST- 2014/05/30 00:00 [pmc-release]
AID - 1755-1536-7-9 [pii]
AID - 10.1186/1755-1536-7-9 [doi]
PST - epublish
SO  - Fibrogenesis Tissue Repair. 2014 May 30;7:9. doi: 10.1186/1755-1536-7-9. 
      eCollection 2014.