Kupffer cell heterogeneity: functional properties of bone marrow–derived and sessile hepatic macrophages

Klein, Ingo; Cornejo, Judith; Polakos, Noelle K.; John, Beena; Wuensch, Sherry A.; Topham, David J.; Pierce, Robert H.; Crispe, Ian Nicholas

doi:10.1182/blood-2007-02-073841

Cited by 291 publications

(278 citation statements)

References 32 publications

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“…Tissue engraftment of bone marrow-derived cells can occur through cell differentiation or cell fusion. 43 For instance, bone marrow cells can give rise to endothelial, smooth muscle reticuloendothelial, and Kupffer cells through differentiation [44][45][46] and skeletal muscle through fusion. 47 However, this field is still controversial 48,49 ; and, in our case, the mechanism remains to be established.…”

Section: Discussionmentioning

confidence: 99%

Successful treatment of the murine model of cystinosis using bone marrow cell transplantation

Syres

Harrison

Tadlock

et al. 2009

Blood

105

103

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Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The defective gene is CTNS encoding the lysosomal cystine transporter, cystinosin. Cystine accumulates in every organ in the body and leads to organ damage and dysfunction, including renal defects. Using the murine model for cystinosis, Ctns ؊/؊ mice, we performed syngeneic bone marrow cell (BMC), hematopoietic stem cell (HSC), and mesenchymal stem cell transplantation. Organ-specific cystine content was reduced by 57% to 94% in all organs tested in the BMC-treated mice. Confocal microscopy and quantitative polymerase chain reaction revealed a large quantity of transplanted BMC in all organs tested, from 5% to 19% of the total cells. Most of these cells were not from the lymphoid lineage but part of the intrinsic structure of the organ. The natural progression of renal dysfunction was prevented, and deposition of corneal cystine crystals was significantly improved in the BMC-treated mice. HSC had the same therapeutic effect as whole BMC. In contrast, mesenchymal stem cell did not integrate efficiently in any organ. This work is a proof of concept for using HSC transplantation as a therapy for cystinosis and highlights the efficiency of this strategy for a chronic, progressive degenerative disease. (Blood. 2009;

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Section: Discussionmentioning

confidence: 99%

Successful treatment of the murine model of cystinosis using bone marrow cell transplantation

Syres

Harrison

Tadlock

et al. 2009

Blood

105

103

View full text Add to dashboard Cite

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“…Single cell suspensions were obtained from mouse livers by perfusion with PBS followed by digestion with 0.05% collagenase type IV (Sigma-Aldrich) as described (58). Single cell suspensions of BMCs were obtained by flushing hind leg femurs and tibias with PBS.…”

Section: Methodsmentioning

confidence: 99%

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

Burdelya

Brackett

Kojouharov

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

175

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Vertebrate Toll-like receptor 5 (TLR5) recognizes bacterial flagellin proteins and activates innate immune responses to motile bacteria. In addition, activation of TLR5 signaling can inhibit growth of TLR5-expressing tumors and protect normal tissues from radiation and ischemia-reperfusion injuries. To understand the mechanisms behind these phenomena at the organismal level, we assessed nuclear factor kappa B (NF-κB) activation (indicative of TLR5 signaling) in tissues and cells of mice treated with CBLB502, a pharmacologically optimized flagellin derivative. This identified the liver and gastrointestinal tract as primary CBLB502 target organs. In particular, liver hepatocytes were the main cell type directly and specifically responding to systemic administration of CBLB502 but not to that of the TLR4 agonist LPS. To assess CBLB502 impact on other pathways, we created multireporter mice with hepatocytes transduced in vivo with reporters for 46 inducible transcription factor families and found that along with NF-κB, CBLB502 strongly activated STAT3-, phenobarbital-responsive enhancer module (PREM), and activator protein 1 (AP-1-) -driven pathways. Livers of CBLB502-treated mice displayed induction of numerous immunomodulatory factors and massive recruitment of various types of immune cells. This led to inhibition of growth of liver metastases of multiple tumors regardless of their TLR5 status. The changed liver microenvironment was not, however, hepatotoxic, because CBLB502 induced resistance to Fas-mediated apoptosis in normal liver cells. Temporary occlusion of liver blood circulation prevented CBLB502 from protecting hematopoietic progenitors in lethally irradiated mice, indicating involvement of a factor secreted by responding liver cells. These results define the liver as the key mediator of TLR5-dependent effects in vivo and suggest clinical applications for TLR5 agonists as hepatoprotective and antimetastatic agents.breast cancer | colon cancer | neutrophils | natural killer cells | Salmonella T oll-like receptors (TLRs) recognize and are activated by specific patterns in molecules that are produced by a broad range of microbial pathogens but are not present in host molecules. Activation of TLRs by these pathogen-associated molecular patterns leads to induction of infection-fighting innate immune responses (1). Various TLR agonists have been considered for multiple clinical applications, including cancer immunotherapy (2-4), and one, the TLR7 agonist imiquimod, is approved for topical treatment of basal cell carcinoma (5).Although signaling pathways induced by different TLRs all result in mobilization of an innate immune response and involve activation of nuclear factor kappa B (NF-κB), the key regulator of immunity (6, 7), TLR5 is a particularly attractive candidate for therapeutic targeting for several reasons. First, bacterial flagellin, the natural ligand of TLR5, was found to have strong radioprotective effects in rodents and nonhuman primates (8). CBLB502 is a rationally designed derivative of Salmon...

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“…In parallel, we transplanted WT bone marrow into Nemo Dhepa (WT-Nemo Dhepa ) and Nemo Dhepa/ TNFR1 À / À (WTNemo Dhepa /TNFR1 À / À ) animals. As previously published, 17 in order to achieve complete replenishment of the Kupffercell population after BMT, we killed the mice, 4 or 48 weeks later, to analyze the contribution of TNFR1 in immune cells to the progression of liver disease (Figure 7a). Chimerism in the liver was confirmed using PCR, which demonstrated successful reconstitution (Figure 7b).…”

Section: Tnfr1 In Chronic Liver Injury Fj Cubero Et Almentioning

confidence: 99%

TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model

et al. 2013

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Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, as well as cancer. Deletion of NF-jB essential modulator in hepatocytes (IKKc/Nemo) causes spontaneous progression of TNF-mediated chronic hepatitis to hepatocellular carcinoma (HCC). Thus, we analyzed the role of death receptors including TNFR1 and TRAIL in the regulation of cell death and the progression of liver injury in IKKc/Nemo-deleted livers. We crossed hepatocyte-specific IKKc/Nemo knockout mice (Nemo Dhepa ) with constitutive TNFR1 À / À and TRAIL À / À mice. Deletion of TNFR1, but not TRAIL, decreased apoptotic cell death, compensatory proliferation, liver fibrogenesis, infiltration of immune cells as well as pro-inflammatory cytokines, and indicators of tumor growth during the progression of chronic liver injury. These events were associated with diminished JNK activation. In contrast, deletion of TNFR1 in bone-marrow-derived cells promoted chronic liver injury. Our data demonstrate that TNF-and not TRAIL signaling determines the progression of IKKc/Nemo-dependent chronic hepatitis. Additionally, we show that TNFR1 in hepatocytes and immune cells have different roles in chronic liver injury-a finding that has direct implications for treating chronic liver disease.

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Kupffer cell heterogeneity: functional properties of bone marrow–derived and sessile hepatic macrophages

Cited by 291 publications

References 32 publications

Successful treatment of the murine model of cystinosis using bone marrow cell transplantation

Successful treatment of the murine model of cystinosis using bone marrow cell transplantation

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model

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