Hepatic recruitment of the inflammatory Gr1<sup>+</sup>monocyte subset upon liver injury promotes hepatic fibrosis

Karlmark, Karlin Raja; Weiskirchen, Ralf; Zimmermann, Henning W.; Gaßler, Nikolaus; Ginhoux, Florent; Weber, Christian; Mérad, Miriam; Luedde, Tom; Trautwein, Christian; Tacke, Frank

doi:10.1002/hep.22950

Cited by 675 publications

(757 citation statements)

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“…This proposed model differs from current paradigms of acute inflammation, where Ly6C hi monocytes are recruited from the circulation to a site of pre-autoimmune injury to become DCs [23][24][25]. In our concept inflammation and organ-specific autoimmunity use different routes for accumulation of DCs in target organs-to-be and suggest that the accumulating DCs in the NOD pancreas are different from the well-characterized TNF/iNOSproducing DCs (TIP-DCs) that are recruited from the peripheral blood to sites of inflammation.…”

Section: Discussionmentioning

confidence: 88%

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

et al. 2011

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The non-obese diabetic (NOD) mouse is a widely used animal model for the study of human diabetes. Before the start of lymphocytic insulitis, DC accumulation around islets of Langerhans is a hallmark for autoimmune diabetes development in this model. Previous experiments indicated that an inflammatory influx of these DCs in the pancreas is less plausible. Here, we investigated whether the pancreas contains DC precursors and whether these precursors contribute to DC accumulation in the NOD pancreas. Fetal pancreases of NOD and control mice were isolated followed by FACS using ER-MP58, Ly6G, CD11b and Ly6C. Sorted fetal pancreatic ER-MP58 1 cells were cultured with GM-CSF and tested for DC markers and antigen processing. CFSE labeling and Ki-67 staining were used to determine cell proliferation in cultures and tissues. Ly6C hi and Ly6C low precursors were present in fetal pancreases of NOD and control mice. These precursors developed into CD11c 1 MHCII 1 CD86 1 DCs capable of processing DQ-OVA. ER-MP58 1 cells in the embryonic and pre-diabetic NOD pancreas had a higher proliferation capacity. Our observations support a novel concept that pre-diabetic DC accumulation in the NOD pancreas is due to aberrant enhanced proliferation of local precursors, rather than to aberrant ''inflammatory infiltration'' from the circulation. IntroductionThe non-obese diabetic (NOD) mouse is used as a spontaneous model to study the development of type 1 diabetes [1]. Lymphocytes accumulate around and in the islets of Langerhans in NOD mice from around 6 weeks of age onwards, which results in the destruction of b-cells followed by a decrease in insulin production leading to diabetes. Prior to T-and B-cell accumulation the number of DCs increases in the pancreas and concentrates around the islets (from the age of 5 weeks onwards) [2,3]. DCs are potent APCs capable of stimulating both naïve and memory T cells [4]. The observation that DCs are the first immune cells to increase in number in the NOD pancreas points to a crucial role for DCs in the initiation of the islet autoimmune reaction. Such a role was recently proven by the demonstration that a temporal depletion of DCs totally abrogated the development of insulitis and diabetes in the NOD mouse model [5].Early studies have shown that BM precursors give rise to monocytes in blood, which circulate for a few days before they migrate into tissue where they develop into different types of DCs and macrophages. Blood monocytes can be subdivided into at least two subsets based on their Ly6C expression: classical and The nonclassical monocytes, which are Ly6C low , patrol the endothelium of the blood vessels and are required for rapid tissue invasion at the site of an infection [7]. Ly6C low monocytes are considered CD11c À , but some studies have reported the expression of CD11c on these cells [6,8]. Both types of monocytes are F4/80 1 and CD86 À [6].Data are accumulating on the presence of local tissue precursors for DCs and macrophages and the contribution of these precursors to DC and ma...

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Section: Discussionmentioning

confidence: 88%

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

et al. 2011

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“…The depletion of CD11b + Gr1 + myeloid cells dramatically aggravated the acute liver injury comparing with secreted IL-1α expression alone, suggesting that the CD11b + Gr1 + myeloid cells play a protective role during acute liver injury and may be a negative feedback induced by secreted IL-1α. Monocytes could be recruited from the blood during acute liver injury and proliferate extensively in the liver [19][20][21]. In order to determine whether secreted IL-1α could enhance the proliferation of CD11b + Gr1 + myeloid cells during acute liver injury, we injected the mice i.p.…”

Section: Secreted Il-1α Promotes the Proliferation Of Cd11b + Gr1 + Mmentioning

confidence: 99%

“…During acute liver injury the intrahepatic macrophages massively expanded because of the influx of peripheral monocytes rather than the proliferation of the tissue-resident macrophages [19][20][21]. Most of these infiltrating monocytes may differentiate to M1 macrophages contributing to liver inflammation [21,22]. However, recent studies challenged this notion by showing local and intrahepatic infiltrating macrophages might be polarized toward M2 phenotype and elicited a protective role by promoting inflammation resolution and tissue repair [19,23,24].…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, increasing evidences showed that hepatic macrophages (kupffer cells) are important players in the propagation of acute liver damage. During acute liver injury the intrahepatic macrophages massively expanded because of the influx of peripheral monocytes rather than the proliferation of the tissue-resident macrophages [19][20][21]. Most of these infiltrating monocytes may differentiate to M1 macrophages contributing to liver inflammation [21,22].…”

Section: Introductionmentioning

confidence: 99%

“…MDSCs may also serve as negative feedback during liver inflammation and their dysfunction could contribute to liver pathology [27,28]. Monocyte migration into the liver is facilitated by the production of CCL2, which is released in the first 1-4 h after the onset of CCl 4 -induced liver injury [21,29,30]. IL-1α can promote CCL2, as well as CCL3, CCL4, CCL5, CXCL2 productions [31,32].…”

Section: Introductionmentioning

confidence: 99%

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Secreted IL‐1α promotes T‐cell activation and expansion of CD11b⁺Gr1⁺ cells in carbon tetrachloride‐induced liver injury in mice

et al. 2015

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Interleukin-1α is mainly expressed on the cell membrane, but can also be secreted during inflammation. The roles of secreted and membrane IL-1α in acute liver inflammation are still not known. Here, we examined the functions of secreted and membrane IL-1α in a mouse model of carbon tetrachloride-induced acute liver injury. We show that secreted IL-1α aggravates liver damage and membrane IL-1α slightly protects mice from liver injury. Further studies showed that secreted IL-1α promotes T-cell activation. It also increased the expansion of CD11b + Gr1 + myeloid cells, which may serve as a negative regulator of acute liver inflammation. Moreover, secreted IL-1α induced IL-6 production from hepatocytes. IL-6 neutralization reduced the proliferation of CD11b + Gr1 + myeloid cells in vivo. CCL2 and CXCL5 expression was increased by secreted IL-1α in vitro and in vivo. Antagonists of the chemokine receptors for CCL2 and CXCL5 significantly reduced the migration of CD11b + Gr1 + myeloid cells. These results demonstrate that secreted and membrane IL-1α play different roles in acute liver injury. Secreted IL-1α could promote Tcell activation and the recruitment and expansion of CD11b + Gr1 + myeloid cells through induction of CCL2, CXCL5, and IL-6. The controlled release of IL-1α could be a critical regulator during acute liver inflammation.Keywords: Acute liver injury r CD11b + Gr1 + myeloid cells r Membrane IL-1α r Secreted IL-1α r T-cell activation Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Haiyan Liu e-mail: hliu@suda.edu.cn IntroductionThe liver plays a central role in metabolic homeostasis [1]. Liver injury is mainly caused by various insults such as drug, chemical agents, viral hepatitis (hepatitis B or C viruses), alcohol, and C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2084-2098 Molecular immunology 2085 autoimmune attack of hepatocytes [2]. Liver damage by proinflammatory cytokines induced by these causes is a relevant mechanism for liver cell death [3]. Acute liver injury remains one of the most challenging problems in liver diseases, and new therapeutic options for treatment of acute liver injury are urgently needed [4]. Carbon tetrachloride (CCl 4 ) is widely used as a chemical inducer of acute or chronic liver injury in rodents depending on the dosage and administration frequency [5]. ROS and oxidative stress are then generated and inflammatory cells are recruited, which leads to hepatocyte degeneration and necrosis [6,7]. Parenchymal cells could regenerate that involves a complex regulated response after CCl 4 -induced acute liver injury [8]. Therefore, anti-oxidative and anti-inflammatory therapies are thought to be the effective ways to prevent and attenuate CCl 4 -induced liver damage. IL-1 is a pleiotropic cytokine and affects inflammatory immune responses. The IL-1 family includes two important agonistic proteins, IL-1α and IL-1β, which play an important role in ...

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Kupffer cells

Kiyani

Seki

2015

Signaling Pathways in Liver Diseases

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Hepatic recruitment of the inflammatory Gr1⁺monocyte subset upon liver injury promotes hepatic fibrosis

Cited by 675 publications

References 35 publications

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b⁺Gr1⁺ cells in carbon tetrachloride‐induced liver injury in mice

Kupffer cells

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Hepatic recruitment of the inflammatory Gr1+monocyte subset upon liver injury promotes hepatic fibrosis

Cited by 675 publications

References 35 publications

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b+Gr1+ cells in carbon tetrachloride‐induced liver injury in mice

Kupffer cells

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Product

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Hepatic recruitment of the inflammatory Gr1⁺monocyte subset upon liver injury promotes hepatic fibrosis

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b⁺Gr1⁺ cells in carbon tetrachloride‐induced liver injury in mice