CCR2 promotes hepatic fibrosis in mice #

Seki, Ekihiro; Minicis, S. De; Inokuchi, Sayaka; Taura, Kojiro; Miyai, Katsumi; Rooijen, Nico van; Schwabe, Robert F.; Brenner, David A.

doi:10.1002/hep.22952

Cited by 377 publications

(358 citation statements)

References 47 publications

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“…There was a moderate, but not significant, reduction of the transcript levels after long-term cultivation, indicating a constitutive expression of CCR2. This result supports the hypothesis that PSCs would be responsive to chemotactic factors that are known to be essentially involved in cell migration [18].…”

Section: Characterization Of In Vitro Propagated Pscs Isolated From Csupporting

confidence: 87%

Bone marrow-derived pancreatic stellate cells in rats

Sparmann

Kruse²,

Hofmeister-Mielke

et al. 2010

Cell Res

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Section: Characterization Of In Vitro Propagated Pscs Isolated From Csupporting

confidence: 87%

Bone marrow-derived pancreatic stellate cells in rats

Sparmann

Kruse²,

Hofmeister-Mielke

et al. 2010

Cell Res

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“…Recent studies have demonstrated that BDL-and CCl 4 -induced fibrosis is markedly reduced in CCR2 Ϫ/Ϫ , CCR1 Ϫ/Ϫ , and TLR4 Ϫ/Ϫ mice. [27][28][29] However, although BM chimeric mice exhibiting CCR2 Ϫ/Ϫ or CCR1 Ϫ/Ϫ BM demonstrated less macrophage and fibrocyte recruitment in response to liver injury, individual deficiency of CCR2 or CCR1 (or TLR4) in hematopoietic cells has little or no effect on extent of hepatic fibrosis.…”

Section: Migration Of Fibrocytes Is Mediated By Chemokine Receptorsmentioning

confidence: 99%

Migration of Fibrocytes in Fibrogenic Liver Injury

Scholten

Reichart

Paik

et al. 2011

The American Journal of Pathology

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100

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CD45 ؉ and collagen I-positive (Col ؉ ) fibrocytes are implicated in fibrogenesis in skin, lungs, and kidneys. Fibrocyte migration in response to liver injury was investigated using bone marrow (BM) from chimeric mice expressing luciferase (Col-Luc¡wt) or green fluorescent protein (Col-GFP¡wt) under control of the ␣1(I) collagen promoter and enhancer, respectively. Monitored by luciferase expression, recruitment of fibrocytes was detected in CCl 4 -damaged liver and in spleen. Migration of CD45 ؉ Col ؉ fibrocytes was regulated by chemokine receptors CCR2 and CCR1, as demonstrated, respectively, by 50% and 25% inhibition of fibrocyte migration in Col-Luc CCR2؊/؊ ¡wt and Col-Luc CCR1؊/؊ ¡wt mice. In addition to CCR2 and CCR1, egress of BM CD45 ؉ Col ؉ cells was regulated by transforming growth factor-␤1 (TGF-␤1) and liposaccharide in vitro and in vivo, which suggests that release of TGF-␤1 and increased intestinal permeability have important roles in fibrocyte trafficking. In the injured liver, fibrocytes gave rise to (myo)fibroblasts. In addition, a BM population of CD45 ؉ Col ؉ cells capable of differentiation into fibrocytes in culture was identified. Egress of CD45 ؉ Col ؉ cells from BM was detected in the absence of injury or stress in aged mice but not in young mice. Development of liver fibrosis was also increased in aged mice and correlated with high numbers of liver fibrocytes. In conclusion, in response to liver injury, fibrocytes migrate from BM to the liver. Their migration is regulated by CCR2 and CCR1 but is compromised with age.

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“…Chemokines, released at the site of injury, stimulate HSC migration by forming a chemotactic gradient. This process is similar to immune cell chemotaxis, and many of the chemokines that stimulate migration of immune cells also stimulate HSC chemotaxis, such as MIP-1a, MIP-1b, RANTES, and MCP-1 [41][42][43]. In addition to these traditional chemokines, various growth factors, such as VEGF and PDGF, and the protein osteopontin stimulate HSC chemotaxis [44][45][46].…”

Section: Mediators That Stimulate Hsc Chemotaxismentioning

confidence: 96%

“…HSCs express the traditional chemokine receptors, Ccr2 and Ccr5, which are activated by MIP-1a, MIP-1b, RAN-TES, and MCP-1 [42,43]. In vitro, HSCs migrate toward these chemokines in a Ccr2-or Ccr5-dependent mechanism, and in vivo, liver fibrosis is reduced in Ccr2 and Ccr5 knockout mice [42,43].…”

Section: Mediators That Stimulate Hsc Chemotaxismentioning

confidence: 99%

“…In vitro, HSCs migrate toward these chemokines in a Ccr2-or Ccr5-dependent mechanism, and in vivo, liver fibrosis is reduced in Ccr2 and Ccr5 knockout mice [42,43]. To distinguish between the role of these receptors on immune cells and non-immune cells, bone marrow from wild-type mice was transplanted into Ccr2 and Ccr5 knockout mice in these studies.…”

Section: Mediators That Stimulate Hsc Chemotaxismentioning

confidence: 99%

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Phenotypic Changes in Hepatic Stellate Cells in Response to Toxic Liver Injury

Copple

2014

Curr Pathobiol Rep

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Hepatic stellate cells (HSCs) are the main extracellular matrix-producing cell type in the liver. These cells exist in a quiescent state in normal liver and an activated state in damaged liver. During quiescence, HSCs store and release various retinoids. After injury to the liver, however, various protein and non-protein mediators are released from cells that stimulate HSCs to differentiate into myofibroblasts, a process termed activation. Activated HSCs begin to express a-smooth muscle actin and migrate to sites of injury through chemotaxis. Within the damaged region of liver, these cells become contractile and produce growth factors that promote hepatocyte replication and angiogenesis, produce extracellular matrix that forms the scaffold for liver repair, and produce proteins that modulate immune cell function. Once liver repair is complete and liver function is restored, HSCs revert back to a quiescent phenotype or die by apoptosis. If liver injury becomes chronic, however, these processes persist resulting in the formation of an extensive scar (i.e., fibrosis) that ultimately leads to liver failure. Because of the importance of these cells to the development of liver fibrosis, there has been extensive research into understanding the mechanisms that drive HSC activation after injury and the mechanisms that regulate reversion of these cells back to quiescence after resolution of injury. In addition, there has been great interest in identifying the various functions of HSCs after acute and chronic injury. The aim of this review is to briefly discuss the phenotypic changes that occur in HSCs after acute and chronic liver injury and to highlight some of the important functions of these cells during repair of the liver.

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CCR2 promotes hepatic fibrosis in mice #

Cited by 377 publications

References 47 publications

Bone marrow-derived pancreatic stellate cells in rats

Bone marrow-derived pancreatic stellate cells in rats

Migration of Fibrocytes in Fibrogenic Liver Injury

Phenotypic Changes in Hepatic Stellate Cells in Response to Toxic Liver Injury

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