Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2

Inflammatory cell infiltration in the liver is a hallmark of nonalcoholic steatohepatitis (NASH). The chemokine-chemokine receptor interaction induces inflammatory cell recruitment. CC-chemokine receptor (CCR)2 is expressed on hepatic macrophages and hepatic stellate cells. This study aims to investigate the therapeutic potential of CCR2 to NASH. Twenty-two weeks on a choline-deficient amino acid-defined (CDAA) diet induced steatosis, inflammatory cell infiltration, and liver fibrosis with increased CCR2 and monocyte chemoattractant protein (MCP)-1 expression in the wild-type livers. The infiltrated macrophages expressed CD68, CCR2, and a marker of bone marrow-derived monocytes, Ly6C. CCR2−/− mice had less steatosis, inflammatory cell infiltration, and fibrosis, and hepatic macrophages expressing CD68 and Ly6C were decreased. Toll-like receptor (TLR)4−/−, TLR9−/−, and MyD88−/− mice had reduced hepatic macrophage infiltration with decreased MCP-1 and CCR2 expression because TLR signaling is a potent inducer of MCP-1. To assess the role of Kupffer cells at the onset of NASH, Kupffer cells were depleted by liposomal clodronate. The Kupffer cell depletion ameliorated steatohepatitis with a decrease in the MCP-1 expression and recruitment of Ly6C-expressing macrophages at the onset of NASH. Finally, to test the therapeutic potential of targeting CCR2, a CCR2 inhibitor was administered to mice on a CDAA diet. The pharmaceutical inhibition of CCR2 prevented infiltration of the Ly6C-positive macrophages, resulting in an inhibition of liver inflammation and fibrosis. We concluded that CCR2 and Kupffer cells contribute to the progression of NASH by recruiting bone marrow-derived monocytes.

Download Full-text

Chemokine Expression Precedes Inflammatory Cell Infiltration and Chemokine Receptor and Cytokine Expression during the Initiation of Murine Lupus Nephritis

Journal of the American Society of Nephrology ◽

10.1681/asn.v1271369 ◽

2001 ◽

Vol 12 (7) ◽

pp. 1369-1382 ◽

Cited By ~ 1

Author(s):

GUILLERMO PÉREZ DE LEMA ◽

HOLGER MAIER ◽

ELENA NIETO ◽

VOLKER VIELHAUER ◽

BRUNO LUCKOW ◽

...

Keyword(s):

Lupus Nephritis ◽

Proinflammatory Cytokines ◽

Chemokine Receptor ◽

Chemokine Receptors ◽

Renal Damage ◽

Inflammatory Cell ◽

Inflammatory Cell Infiltration ◽

Cell Infiltration ◽

Mononuclear Cell Infiltration ◽

Monocyte Chemoattractant Protein 1

Abstract. Lupus nephritis is characterized by immune complex deposition and inflammatory cell infiltration. Therefore, the initiation and progression of lupus nephritis in MRL/MpJ Faslpr/lpr(MRL/lpr) mice were investigated, with a focus on the expression of several chemokines and chemokine receptors. Mice were monitored for proteinuria from 6 to 20 wk of age, and kidneys were examined every 2 wk by light microscopy, electron microscopy, and immunohistologic analyses. Furthermore, the expression of chemokines, chemokine receptors, and proinflammatory cytokines was analyzed in ribonuclease protection assays. MRL/lpr mice demonstrated increased expression of monocyte chemoattractant protein-1, regulated upon activation, normal T cell-expressed and -secreted protein, inducible protein of 10 kD, and macrophage inflammatory protein-1β at week 8. At that time point, levels of circulating and glomerular immune complexes were increased, and no proteinuria or histopathologic signs of renal damage could be observed. As assessed in immunohistochemical andin situhybridization analyses, monocyte chemoattractant protein-1 and regulated upon activation, normal T cell-expressed and -secreted protein expression was preferentially located in the glomeruli and interstitium. Mononuclear cell infiltration of the kidney was observed by weeks 10 to 12. At week 12, the renal expression of chemokine receptor 1 (CCR1), CCR2, and CCR5 was increased, mice became proteinuric, and renal damage was histologically evident. Finally, the expression of proinflammatory cytokines was detected (weeks 12 to 14). In summary, (1) chemokines are upregulated before inflammatory cell infiltration, proteinuria, and kidney damage are observed; (2) chemokine generation is restricted to sites of subsequent inflammatory cell infiltration,i.e., glomeruli and interstitium; (3) chemokine receptor expression parallels mononuclear cell infiltration; and (4) proinflammatory cytokines are upregulated later, in parallel with inflammatory cell infiltration and the onset of proteinuria. These results support the hypothesis that chemokines initiate leukocyte infiltration and precede proteinuria and renal damage in MRL/lpr mice.

Download Full-text

Cathepsin B deficiency ameliorates liver lipid deposition, inflammatory cell infiltration, and fibrosis after diet-induced nonalcoholic steatohepatitis

Translational Research ◽

10.1016/j.trsl.2020.04.011 ◽

2020 ◽

Vol 222 ◽

pp. 28-40 ◽

Cited By ~ 1

Author(s):

Wenqian Fang ◽

Zhiyong Deng ◽

Feriel Benadjaoud ◽

Chongzhe Yang ◽

Guo-Ping Shi

Keyword(s):

Nonalcoholic Steatohepatitis ◽

Cathepsin B ◽

Inflammatory Cell ◽

Liver Lipid ◽

Inflammatory Cell Infiltration ◽

Cell Infiltration ◽

Lipid Deposition

Download Full-text

CCR3 Gene Knockout in Bone Marrow Cells Ameliorates Combined Allergic Rhinitis and Asthma Syndrome (CARAS) by Reducing Airway Inflammatory Cell Infiltration and Th2 Cytokines Expression in Mice Model

SSRN Electronic Journal ◽

10.2139/ssrn.3954755 ◽

2021 ◽

Author(s):

MeiNa Dai ◽

XinHua Zhu ◽

Juan Yu ◽

JiaSheng Yuan ◽

Yv Zhu ◽

...

Keyword(s):

Bone Marrow ◽

Allergic Rhinitis ◽

Inflammatory Cell ◽

Bone Marrow Cells ◽

Gene Knockout ◽

Inflammatory Cell Infiltration ◽

Cell Infiltration ◽

Th2 Cytokines ◽

Mice Model ◽

Marrow Cells

Download Full-text

Muscle paralysis induces bone marrow inflammation and predisposition to formation of giant osteoclasts

AJP Cell Physiology ◽

10.1152/ajpcell.00363.2016 ◽

2017 ◽

Vol 313 (5) ◽

pp. C533-C540 ◽

Cited By ~ 2

Author(s):

Brandon J. Ausk ◽

Leah E. Worton ◽

Kate S. Smigiel ◽

Ronald Y. Kwon ◽

Steven D. Bain ◽

...

Keyword(s):

Bone Marrow ◽

Bone Resorption ◽

Time Course ◽

Inflammatory Cell ◽

Botulinum Toxin A ◽

Inflammatory Cell Infiltration ◽

Cell Infiltration ◽

Muscle Paralysis ◽

Inflammatory Microenvironment ◽

Tibia Bone

Transient muscle paralysis engendered by a single injection of botulinum toxin A (BTxA) rapidly induces profound focal bone resorption within the medullary cavity of adjacent bones. While initially conceived as a model of mechanical disuse, osteoclastic resorption in this model is disproportionately severe compared with the modest gait defect that is created. Preliminary studies of bone marrow following muscle paralysis suggested acute upregulation of inflammatory cytokines, including TNF-α and IL-1. We therefore hypothesized that BTxA-induced muscle paralysis would rapidly alter the inflammatory microenvironment and the osteoclastic potential of bone marrow. We tested this hypothesis by defining the time course of inflammatory cell infiltration, osteoinflammatory cytokine expression, and alteration in osteoclastogenic potential in the tibia bone marrow following transient muscle paralysis of the calf muscles. Our findings identified inflammatory cell infiltration within 24 h of muscle paralysis. By 72 h, osteoclast fusion and pro-osteoclastic inflammatory gene expression were upregulated in tibia bone marrow. These alterations coincided with bone marrow becoming permissive to the formation of osteoclasts of greater size and greater nuclei numbers. Taken together, our data are consistent with the thesis that transient calf muscle paralysis induces acute inflammation within the marrow of the adjacent tibia and that these alterations are temporally consistent with a role in mediating muscle paralysis-induced bone resorption.

Download Full-text

The Influence of Bone Marrow-Secreted IL-10 in a Mouse Model of Cerulein-Induced Pancreatic Fibrosis

BioMed Research International ◽

10.1155/2016/4601532 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Wey-Ran Lin ◽

Siew-Na Lim ◽

Tzung-Hai Yen ◽

Malcolm R. Alison

Keyword(s):

Bone Marrow ◽

Mouse Model ◽

Inflammatory Cell ◽

Inflammatory Cell Infiltration ◽

Pancreatic Fibrosis ◽

Cell Infiltration ◽

Collagen Deposition ◽

Wild Type

This study aimed to understand the role of IL-10 secreted from bone marrow (BM) in a mouse model of pancreatic fibrosis. The severity of cerulein-induced inflammation, fibrosis, and the frequency of BM-derived myofibroblasts were evaluated in the pancreas of mice receiving either a wild-type (WT) BM or an IL-10 knockout (KO) BM transplantation. The area of collagen deposition increased significantly in the 3 weeks after cerulein cessation in mice with an IL-10 KO BM transplant (13.7 ± 0.6% and 18.4 ± 1.1%,p< 0.05), but no further increase was seen in WT BM recipients over this time. The percentage of BM-derived myofibroblasts also increased in the pancreas of the IL-10 KO BM recipients after cessation of cerulein (6.7 ± 1.1% and 11.9 ± 1.3%,p< 0.05), while this figure fell in WT BM recipients after cerulein withdrawal. Furthermore, macrophages were more numerous in the IL-10 KO BM recipients than the WT BM recipients after cerulein cessation (23.2 ± 2.3 versus 15.3 ± 1.7 per HPF,p< 0.05). In conclusion, the degree of fibrosis, inflammatory cell infiltration, and the number of BM-derived myofibroblasts were significantly different between IL-10 KO BM and WT BM transplanted mice, highlighting a likely role of IL-10 in pancreatitis.

Download Full-text

The therapeutic potential of C-C chemokine receptor antagonists in nonalcoholic steatohepatitis

Exploration of Medicine ◽

10.37349/emed.2020.00012 ◽

2020 ◽

Vol 1 (4) ◽

pp. 170-183

Author(s):

Michael Doulberis ◽

Kasiani Papadimitriou ◽

Apostolis Papaefthymiou ◽

Jannis Kountouras ◽

Stergios A. Polyzos

Keyword(s):

Kupffer Cells ◽

Chemokine Receptor ◽

Nonalcoholic Steatohepatitis ◽

Therapeutic Potential ◽

Hepatic Inflammation ◽

Dual Inhibitor ◽

Nonalcoholic Fatty Liver ◽

Pooled Prevalence ◽

Immunodeficiency Virus ◽

Monocytes And Macrophages

Pooled prevalence of nonalcoholic fatty liver disease (NAFLD) globally is about 25%. Nonalcoholic steatohepatitis (NASH) with advanced fibrosis has been linked with substantial morbidity and mortality, without having to-date any licensed treatment. C-C chemokine receptor (CCR) antagonists have been investigated as candidates for the treatment of NASH. Inhibition of CCR2 is expected to mitigate hepatic inflammation, through reducing the activation of Kupffer cells, as well as the infiltration of monocytes and macrophages into the liver. Inhibition of CCR5 is expected to mitigate hepatic fibrogenesis, through impairing the activation of hepatic stellate cells, as well as to mitigate hepatic inflammation, through impairing the activation of Kupffer cells and macrophages. Cenicriviroc (CVC) is the first in class, dual inhibitor of CCR2 and CCR5. After exhibiting favorable results in animal models, CVC was shown to be beneficial in NASH patients with more severe fibrosis at a phase 2b trial (CENTAUR) and is currently at a phase 3 clinical trial (AURORA). Apart from CVC, other CCR5 mono-antagonists, such as maraviroc, are under evaluation in clinical trials with human immunodeficiency virus patients with NAFLD. The aim of this review was to summarize existing evidence on CVC and other CCR antagonists in NASH patients, primarily focusing on their clinical efficacy and safety.

Download Full-text