Kupffer cells and activation of endothelial TLR4 coordinate neutrophil adhesion within liver sinusoids during endotoxemia

2013 ◽  
Vol 305 (11) ◽  
pp. G797-G806 ◽  
Author(s):  
Braedon McDonald ◽  
Craig N. Jenne ◽  
Lisheng Zhuo ◽  
Koji Kimata ◽  
Paul Kubes
Keyword(s):  
Bone Marrow ◽  
Kupffer Cells ◽  
Inflammatory Responses ◽  
Vascular Dysfunction ◽  
Neutrophil Recruitment ◽  
Neutrophil Adhesion ◽  
Pathological Feature ◽  
Liver Sinusoids ◽  
Adhesive Interactions ◽  
Tlr4 Activation

A key pathological feature of the systemic inflammatory response of sepsis/endotoxemia is the accumulation of neutrophils within the microvasculature of organs such as the liver, where they cause tissue damage and vascular dysfunction. There is emerging evidence that the vascular endothelium is critical to the orchestration of inflammatory responses to blood-borne microbes and microbial products in sepsis/endotoxemia. In this study, we aimed to understand the role of endothelium, and specifically endothelial TLR4 activation, in the regulation of neutrophil recruitment to the liver during endotoxemia. Intravital microscopy of bone marrow chimeric mice revealed that TLR4 expression by non-bone marrow-derived cells was required for neutrophil recruitment to the liver during endotoxemia. Furthermore, LPS-induced neutrophil adhesion in liver sinusoids was equivalent between wild-type mice and transgenic mice that express TLR4 only on endothelium ( tlr4−/−Tie2 tlr4), revealing that activation of endothelial TLR4 alone was sufficient to initiate neutrophil adhesion. Neutrophil arrest within sinusoids of endotoxemic mice requires adhesive interactions between neutrophil CD44 and endothelial hyaluronan. Intravital immunofluorescence imaging demonstrated that stimulation of endothelial TLR4 alone was sufficient to induce the deposition of serum-derived hyaluronan-associated protein (SHAP) within sinusoids, which was required for CD44/hyaluronan-dependent neutrophil adhesion. In addition to endothelial TLR4 activation, Kupffer cells contribute to neutrophil recruitment via a distinct CD44/HA/SHAP-independent mechanism. This study sheds new light on the control of innate immune activation within the liver vasculature during endotoxemia, revealing a key role for endothelial cells as sentinels in the detection of intravascular infections and coordination of neutrophil recruitment to the liver.

INTERACTION OF CD44 AND HYALURONAN IS THE DOMINANT MECHANISM FOR NEUTROPHIL ADHESION IN INFLAMED LIVER SINUSOIDS

2008 ◽  
Vol 31 (4) ◽  
pp. 16
Author(s):  
Braedon McDonald ◽  
Erin F McAvoy ◽  
Florence Lam ◽  
Varinder Gill ◽  
Paul Kubes
Keyword(s):  
Adhesion Molecules ◽  
Intravital Microscopy ◽  
Inflammatory Responses ◽  
Flow Chamber ◽  
Neutrophil Recruitment ◽  
Neutrophil Adhesion ◽  
Antibody Technique ◽  
Liver Sinusoids

Background: Previous studies have been unable to identify adhesion molecules that mediate neutrophil recruitment within the liver sinusoids. We hypothesise that involved adhesion molecules may represent novel therapeutic targets for combating pathologic liver inflammation. Methods: Candidate adhesion molecules were identified using a novel in vivo biopanning approach (dual radiolabelled antibody technique) to quantify endothelial expression levels within the liver compared to other organs. Spinning disk intravital microscopy demonstrated the localization of adhesion molecule expression withinthe liver microvasculature. Using knockout mice, bone marrow chimeric mice, and blocking antibodies, candidate adhesion molecules were systematically investigated for a role in neutrophil recruitment in the liver sinusoids of endotoxemic mice using intravital microscopy and in vitro flow chamber assays. Results: Hyaluronan was identified as disproportionately expressed in the liver versus other organs, and hyaluronan expression was restricted to liver sinusoids. Blocking CD44-hyaluronan interactions reduced neutrophil adhesion in the sinusoids of endotoxemic mice, but had no effect on neutrophil rolling or adhesion in post-sinusoidal venules. Neutrophil but not endothelial CD44 was required for adhesionin sinusoids. Surprisingly, neutrophil CD44 avidity for hyaluronan was not increased in endotoxemia. Instead, activation of CD44-hyaluronan engagement was the result of qualitative modification of hyaluronan by a dramatic induction of serum-derived hyaluronan-associated protein (SHAP) in sinusoids in response to lipopolysaccharide. Lipopolysaccharide-induced hepatic injury was significantly reduced by inhibiting CD44-hyaluronan interactions. Therapeutic administration of anti-CD44 antibody to endotoxemic mice rapidly detached adherent neutrophils and improved sinusoidal perfusion. Conclusion: These findings reveal CD44 as a potential therapeutic target in systemic inflammatory responses involving liver.

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

Blood ◽  
2007 ◽  
Vol 110 (12) ◽  
pp. 4077-4085 ◽  
Author(s):  
Ingo Klein ◽  
Judith C. Cornejo ◽  
Noelle K. Polakos ◽  
Beena John ◽  
Sherry A. Wuensch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell Activation ◽  
Kupffer Cells ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Heterogeneity ◽  
Blood Monocytes ◽  
Liver Sinusoids ◽  
Hepatic Macrophages ◽  
Experimental Approaches

Abstract Kupffer cells form a large intravascular macrophage bed in the liver sinusoids. The differentiation history and diversity of Kupffer cells is disputed; some studies argue that they are derived from blood monocytes, whereas others support a local origin from intrahepatic precursor cells. In the present study, we used both flow cytometry and immunohistochemistry to distinguish 2 subsets of Kupffer cells that were revealed in the context both of bone marrow transplantation and of orthotopic liver transplantation. One subset was radiosensitive and rapidly replaced from hematogenous precursors, whereas the other was relatively radioresistant and long-lived. Both were phagocytic but only the former population was recruited into inflammatory foci in response to CD8+ T-cell activation. We propose the name “sessile” for the radioresistant Kupffer cells that do not participate in immunoinflammatory reactions. However, we found no evidence that these sessile Kupffer cells arise from immature intrahepatic precursors. Our conclusions resolve a long-standing controversy and explain how different experimental approaches may reveal one or both of these subsets.

scholarly journals Luteolin transforms the polarity of bone marrow-derived macrophages to regulate the cytokine storm

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Shuxia Wang ◽  
Shuhang Xu ◽  
Jing Zhou ◽  
Li Zhang ◽  
Xiaodong Mao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Inflammatory Responses ◽  
Bone Marrow Cells ◽  
Membrane Surface ◽  
Inflammatory Factors ◽  
Mouse Bone Marrow ◽  
Macrophage Polarisation ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
M1 Type

Abstract Background Macrophages are indispensable regulators of inflammatory responses. Macrophage polarisation and their secreted inflammatory factors have an association with the outcome of inflammation. Luteolin, a flavonoid abundant in plants, has anti-inflammatory activity, but whether luteolin can manipulate M1/M2 polarisation of bone marrow-derived macrophages (BMDMs) to suppress inflammation is still unclear. This study aimed to observe the effects of luteolin on the polarity of BMDMs derived from C57BL/6 mice and the expression of inflammatory factors, to explore the mechanism by which luteolin regulates the BMDM polarity. Methods M1-polarised BMDMs were induced by lipopolysaccharide (LPS) + interferon (IFN)-γ and M2-polarisation were stimulated with interleukin (IL)-4. BMDM morphology and phagocytosis were observed by laser confocal microscopy; levels of BMDM differentiation and cluster of differentiation (CD)11c or CD206 on the membrane surface were assessed by flow cytometry (FCM); mRNA and protein levels of M1/M2-type inflammatory factors were performed by qPCR and ELISA, respectively; and the expression of p-STAT1 and p-STAT6 protein pathways was detected by Western-blotting. Results The isolated mouse bone marrow cells were successfully differentiated into BMDMs, LPS + IFN-γ induced BMDM M1-phenotype polarisation, and IL-4 induced M2-phenotype polarisation. After M1-polarised BMDMs were treated with luteolin, the phagocytosis of M1-polarized BMDMs was reduced, and the M1-type pro-inflammatory factors including IL-6, tumour necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), and CD86 were downregulated while the M2-type anti-inflammatory factors including IL-10, IL-13, found in inflammatory zone (FIZZ)1, Arginase (Arg)1 and CD206 were upregulated. Additionally, the expression of M1-type surface marker CD11c decreased. Nevertheless, the M2-type marker CD206 increased; and the levels of inflammatory signalling proteins phosphorylated signal transducer and activator of transcription (p-STAT)1 and p-STAT6 were attenuated and enhanced, respectively. Conclusions Our study suggests that luteolin may transform BMDM polarity through p-STAT1/6 to regulate the expression of inflammatory mediators, thereby inhibiting inflammation. Naturally occurring luteolin holds promise as an anti-inflammatory and immunomodulatory agent.

scholarly journals Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chia-Ching Lin ◽  
Yi-Ru Shen ◽  
Chi-Chih Chang ◽  
Xiang-Yi Guo ◽  
Yun-Yun Young ◽  
...  
Keyword(s):  
Posttranscriptional Regulation ◽  
Inflammatory Responses ◽  
Rna Stability ◽  
Innate Immune ◽  
Stem Loop ◽  
Stem Loop Structure ◽  
Tlr4 Activation ◽  
Harmful Effects ◽  
Different Levels

AbstractDifferent levels of regulatory mechanisms, including posttranscriptional regulation, are needed to elaborately regulate inflammatory responses to prevent harmful effects. Terminal uridyltransferase 7 (TUT7) controls RNA stability by adding uridines to its 3′ ends, but its function in innate immune response remains obscure. Here we reveal that TLR4 activation induces TUT7, which in turn selectively regulates the production of a subset of cytokines, including Interleukin 6 (IL-6). TUT7 regulates IL-6 expression by controlling ribonuclease Regnase-1 mRNA (encoded by Zc3h12a gene) stability. Mechanistically, TLR4 activation causes TUT7 to bind directly to the stem-loop structure on Zc3h12a 3′-UTR, thereby promotes Zc3h12a uridylation and degradation. Zc3h12a from LPS-treated TUT7-sufficient macrophages possesses increased oligo-uridylated ends with shorter poly(A) tails, whereas oligo-uridylated Zc3h12a is significantly reduced in Tut7-/- cells after TLR4 activation. Together, our findings reveal the functional role of TUT7 in sculpting TLR4-driven responses by modulating mRNA stability of a selected set of inflammatory mediators.

The Fate of Bone Marrow Lesions After Open Wedge High Tibial Osteotomy: A Comparison Between Knees With Primary Osteoarthritis and Subchondral Insufficiency Fractures

2021 ◽  
pp. 036354652110021
Author(s):  
Han Gyeol Choi ◽  
Joo Sung Kim ◽  
Hyun Jin Yoo ◽  
You Sun Jung ◽  
Yong Seuk Lee
Keyword(s):  
Bone Marrow ◽  
High Tibial Osteotomy ◽  
Insufficiency Fracture ◽  
Tibial Osteotomy ◽  
Pathological Feature ◽  
Open Wedge ◽  
Varus Malalignment ◽  
Bone Marrow Lesions ◽  
Wedge High Tibial Osteotomy

Background: Subchondral insufficiency fracture of the knee (SIFK) is characterized by a subchondral lesion that may lead to end-stage osteoarthritis (OA). In patients who have SIFK in a precollapse state with varus malalignment, a joint-preserving technique such as open wedge high tibial osteotomy (OWHTO) should be considered. Purpose: To evaluate the efficacy of OWHTO in primary OA and SIFK-dominant OA by clinical and radiological evaluations including magnetic resonance imaging (MRI). Study Design: Cohort study; Level of evidence 3. Methods: A total of 33 SIFK-dominant OA knees and 66 with primary OA that underwent biplanar OWHTO between March 2014 and February 2016 were included after 1:2 propensity score matching. The MRI Osteoarthritis Knee Score was used to assess bone marrow lesions (BMLs) preoperatively and at follow-up. The weightbearing line ratio, the hip-knee-ankle angle, and the joint line convergence angle were measured. The clinical outcomes assessed were range of motion, the American Knee Society Score, and the Western Ontario and McMaster University (WOMAC) score. Results: The mean follow-up period was 41.2 ± 12.6 months. The distribution of preoperative BML grade in the SIFK-dominant OA group was significantly higher in both the femur and tibia ( P < .001 and <.001, respectively) than that in the primary OA group. However, the difference was not significant postoperatively (femur, P = .425; tibia, P = .462). In both groups, postoperative BMLs showed significant improvement compared with preoperative BMLs (primary OA [femur, P < .001; tibia, P = .001] and SIFK-dominant OA [femur, P < .001; tibia, P < .001]). The WOMAC pain score was higher in the SIFK-dominant OA group preoperatively (primary OA, 7.0 ± 3.73; SIFK-dominant OA, 9.17 ± 2.6; P = .032) even though it was not different at the final follow-up (primary OA, 2.11 ± 1.7; SIFK-dominant OA, 1.79 ± 1.32; P = .179). Conclusion: OWHTO is an effective procedure not only for primary OA but also for SIFK-dominant OA. OWHTO can improve BMLs, which represent the main pathological feature of SIFK. Therefore, in patients who have SIFK with varus malalignment, OWHTO can be an attractive treatment option for preserving the joint and enhancing subchondral bone healing.

N-cadherin is developmentally regulated and functionally involved in early hematopoietic cell differentiation

2001 ◽  
Vol 114 (8) ◽  
pp. 1567-1577 ◽  
Author(s):  
S. Puch ◽  
S. Armeanu ◽  
C. Kibler ◽  
K.R. Johnson ◽  
C.A. Muller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Adhesion ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Classical Type ◽  
Type I ◽  
Facs Analysis ◽  
Hematopoietic Progenitors ◽  
Developmentally Regulated ◽  
Adhesive Interactions

The cadherins, an important family of cell adhesion molecules, are known to play major roles during embryonic development and in the maintenance of solid tissue architecture. In the hematopoietic system, however, little is known of the role of this cell adhesion family. By RT-PCR, western blot analysis and immunofluorescence staining we show that N-cadherin, a classical type I cadherin mainly expressed on neuronal, endothelial and muscle cells, is expressed on the cell surface of resident bone marrow stromal cells. FACS analysis of bone marrow mononuclear cells revealed that N-cadherin is also expressed on a subpopulation of early hematopoietic progenitor cells. Triple-color FACS analysis defined a new CD34(+) CD19(+) N-cadherin(+) progenitor cell population. During further differentiation, however, N-cadherin expression is lost. Treatment of CD34(+) progenitor cells with function-perturbing N-cadherin antibodies drastically diminished colony formation, indicating a direct involvement of N-cadherin in the differentiation program of early hematopoietic progenitors. N-cadherin can also mediate adhesive interactions within the bone marrow as demonstrated by inhibition of homotypic interactions of bone-marrow-derived cells with N-cadherin antibodies. Together, these data strongly suggest that N-cadherin is involved in the development and retention of early hematopoietic progenitors within the bone marrow microenvironment.

Loss of Membrane Expression of E-Cadherin in Leukemic Erythroblasts

2001 ◽  
Vol 125 (2) ◽  
pp. 198-201
Author(s):  
Geza Acs ◽  
Virginia A. LiVolsi
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Bone Marrow Aspirate ◽  
Hematopoietic Cells ◽  
Immunoperoxidase Staining ◽  
Membrane Expression ◽  
Biopsy Specimens ◽  
Erythroid Precursors ◽  
Adhesive Interactions ◽  
E Cadherin

Abstract Context.—The special societal relationships existing between various cell types in bone marrow suggests that there may be a link between the adhesive characteristics of hematopoietic cells and their maturation. Egress of the developing hematopoietic cells is also a highly regulated process governed by adhesive interactions. In leukemia, immature blasts are not retained within the marrow, suggesting a breakdown of adhesive mechanisms. Recent reports suggest that E-cadherin, an epithelial adhesion molecule, is expressed on erythroid precursors and megakaryocytes, but not on other hematopoietic marrow elements. Objective.—To characterize the expression pattern of E-cadherin in normal and leukemic erythroid precursors by immunohistochemistry in paraffin-embedded tissue and bone marrow aspirate smears. Methods.—Five normal bone marrow specimens from rib resections, 15 trephine bone marrow biopsy specimens, and 6 bone marrow aspirate smears from the iliac crest of patients with no known leukemia were selected. Fourteen bone marrow biopsy specimens from patients with erythroleukemia were also studied. Immunoperoxidase staining of paraffin-embedded tissue and air-dried aspirate smears for E-cadherin (1:200 dilution, HECD-1 clone) was performed using the avidin-biotin peroxidase technique. Results.—In paraffin-embedded bone marrow biopsy and rib specimens and in air-dried bone marrow aspirate smears, strong membrane expression of E-cadherin was seen in the normal erythroid precursors in all cases. In contrast, no membrane expression of E-cadherin was present in any of the bone marrow biopsy specimens from patients with erythroleukemia. Conclusions.—Immunohistochemical detection of membrane expression of E-cadherin may be a useful tool for identification of erythroid precursors. Cells of erythroleukemia lack membrane expression of E-cadherin, in contrast to their normal counterparts. Further studies are needed to define the potential role of E-cadherin in the maturation of erythroid precursors and to ascertain the significance of loss of membrane expression of E-cadherin in erythroleukemia.

Fate alteration of bone marrow-derived macrophages ameliorates kidney fibrosis in murine model of unilateral ureteral obstruction

2018 ◽  
Vol 34 (10) ◽  
pp. 1657-1668 ◽  
Author(s):  
Ying Yang ◽  
Xiaojian Feng ◽  
Xinyan Liu ◽  
Ying Wang ◽  
Min Hu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Kidney Diseases ◽  
Unilateral Ureteral Obstruction ◽  
Immunofluorescent Staining ◽  
Enzyme Linked Immunosorbent Assay ◽  
Pathological Feature ◽  
Kidney Fibrosis ◽  
Anti Inflammatory

AbstractBackgroundRenal fibrosis is a key pathological feature and final common pathway leading to end-stage kidney failure in many chronic kidney diseases. Myofibroblast is the master player in renal fibrosis. However, myofibroblasts are heterogeneous. Recent studies show that bone marrow-derived macrophages transform into myofibroblasts by transforming growth factor (TGF)-β-induced macrophage–myofibroblast transition (MMT) in renal fibrosis.MethodsTGF-β signaling was redirected by inhibition of β-catenin/T-cell factor (TCF) to increase β-catenin/Foxo in bone marrow-derived macrophages. A kidney fibrosis model of unilateral ureteral obstruction was performed in EGFP bone marrow chimera mouse. MMT was examined by flow cytometry analysis of GFP+F4/80+α-SMA+ cells from unilateral ureteral obstruction (UUO) kidney, and by immunofluorescent staining of bone marrow-derived macrophages in vitro. Inflammatory and anti-inflammatory cytokines were analysis by enzyme-linked immunosorbent assay.ResultsInhibition of β-catenin/TCF by ICG-001 combined with TGF-β1 treatment increased β-catenin/Foxo1, reduced the MMT and inflammatory cytokine production by bone marrow-derived macrophages, and thereby, reduced kidney fibrosis in the UUO model.ConclusionsOur results demonstrate that diversion of β-catenin from TCF to Foxo1-mediated transcription not only inhibits the β-catenin/TCF-mediated fibrotic effect of TGF-β, but also enhances its anti-inflammatory action, allowing therapeutic use of TGF-β to reduce both inflammation and fibrosis at least partially by changing the fate of bone marrow-derived macrophages.

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