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PubMed1986

Molecular basis of macrophage activation. Expression of the low potential cytochrome b and its reduction upon cell stimulation in activated macrophages.

The expression of the novel b-type cytochrome, which is part of the superoxide anion (O2-)-generating system in phagocytes, has been investigated in population of mouse peritoneal macrophages heterogeneous in their capability to produce O2-). Reduced minus oxidized difference spectra of intact cells showed the appearance of a b-type cytochrome with major peaks in the alpha region at 558 to 559 nm and in the gamma region at 426 to 428 nm. Resident peritoneal macrophages, as well as thioglycollate broth-elicited and Corynebacterium Parvum-activated macrophages and neutrophils expressed about 50 pmol cytochrome b/10(7) cells. In intact macrophages and neutrophils, Na-dithionite reduced greater than 75% of the cytochrome b measurable in disrupted cells. No correlation was found between capability to produce O2-) by different population of macrophages and their content of cytochrome b. When stimulated in strictly anaerobic conditions with phorbol myristic acetate, macrophages activated in vivo by i.p. injection of Corynebacterium Parvum reduced approximately 40% of their total cytochrome b. In resident peritoneal macrophages that produced five times lower amounts of O2-, cytochrome b reduction was instead undetectable. Potentiometric properties of cytochrome b was investigated in macrophage subcellular particles. Both resident and Corynebacterium Parvum-activated macrophages revealed the presence of b chromophores with very low potentials of -255 and -244 mV, respectively, whose content was not different in the two populations. These results show that resident and activated macrophages express the same amount of cytochrome b, but upon stimulation with PMA, activated macrophages recruit a higher number of cytochrome b molecules in parallel with an enhanced production of O2-.

Animals↗
PubMed1984

Macrophage activation to kill Leishmania tropica: characterization of P/J mouse macrophage defects for lymphokine-induced antimicrobial activities against Leishmania tropica amastigotes.

Macrophages from P/J mice demonstrated both quantitative and qualitative defects in lymphokine (LK)-induced activated macrophage antileishmanial effector reactions: a) these cells recognized the same LK signals that generated resistance to infection in responsive C3H/HeN macrophages, but more signal was required to observe maximal activity; b) LK-induced intracellular destruction of Leishmania tropica by P/J macrophages was minimal (less than 20%), and was induced by only one of three LK signals that regulate antimicrobial activities in C3H/HeN macrophages. The defective microbicidal activity of P/J macrophages observed with LK activation in vitro could also be demonstrated in vivo. Macrophages from P/J mice exposed to the macrophage-activating agent Mycobacterium bovis strain BCG in vivo were capable of restricting the intracellular replication of L. tropica but could not eliminate intracellular parasites, even with further incubation with LK during the 72-hr culture period. The defect of P/J macrophages for intracellular destruction of L. tropica, then, occurred in the activation sequence before the triggering stage that characterizes the macrophage defect of C3H/HeJ mice. Genetic regulation of the P/J macrophage defect appears to be by a single autosomal gene, with defective microbicidal activity as a recessive trait in these animals.

Animals↗
PubMed1998

Macrophage colony-stimulating factor stimulates synthesis and secretion of a mouse homolog of a human IgE-dependent histamine-releasing factor by macrophages in vitro and in vivo.

Treatment of murine resident peritoneal macrophages with macrophage-CSF (M-CSF) up-regulated the synthesis of a discrete set of proteins, including a 26-kDa protein (p26). The sequence of 20 NH2-terminal amino acids of the purified p26 was identical with the mouse homolog of a human IgE-dependent histamine-releasing factor (HRF). Among macrophage activators tested (M-CSF, granulocyte-macrophage-CSF, IL-3, TNF-alpha, IFN-gamma, and LPS), only M-CSF could up-regulate the p26 HRF synthesis by cultured macrophages. M-CSF not only increased the levels of p26 HRF mRNA and protein, but also stimulated the secretion of an N-glycosylated p26 HRF with a m.w. of 30 kDa. Repeated injections of M-CSF into mouse peritoneal cavity for 4 days elicited macrophages expressing abundant p26 HRF. A single i.p. injection of M-CSF failed to increase the p26 HRF level in peritoneal macrophages of thioglycollate-, LPS-, or adjuvant-treated mice, while M-CSF challenge to OVA-immunized mice caused macrophage infiltration and overproduction of p26 HRF, similarly as did OVA challenge. The Ag-specific priming for enhanced synthesis and secretion of p26 HRF by M-CSF was also demonstrated in cultured macrophages prepared from OVA-immunized mice. An i.p. injection of M-CSF or recombinant p26 HRF triggered eosinophil recruitment, even in the absence of the Ag, in the sensitized mice, but not in normal mice. Furthermore, recombinant p26 HRF could induce eosinophilia without marked macrophage and lymphocyte infiltrations. Our results suggest that p26 HRF secreted by M-CSF-stimulated macrophages may be an important mediator for the late phase allergic inflammation.

Animals↗
PubMed2000

Macrophage colony-stimulating factor antagonists inhibit replication of HIV-1 in human macrophages.

Macrophages infected with HIV-1 produce high levels of M-CSF and macrophage-inflammatory protein-1alpha (MIP-1alpha). M-CSF facilitates the growth and differentiation of macrophages, while the chemotactic properties of MIP-1alpha attract both T lymphocytes and macrophages to the site of HIV infection. Studies described in this work indicate M-CSF may function in an autocrine/paracrine manner to sustain HIV replication, and data suggest possible therapeutic strategies for decreasing viral load following HIV infection. We show that macrophage infection with measles virus or respiratory syncytial virus, in contrast to HIV-1, results in production of MIP-1alpha, but not M-CSF. Thus, M-CSF appears to be specifically produced upon infection of macrophages with HIV-1. Furthermore, addition of M-CSF antagonists to HIV-1-infected macrophages, including anti-M-CSF monoclonal or polyclonal Abs or soluble M-CSF receptors, dramatically inhibited HIV-1 replication and reduced production of MIP-1alpha. Our results suggest that biologic antagonists for M-CSF may represent novel strategies for inhibiting the spread of HIV-1 by 1) blocking virus replication in macrophages, 2) reducing recruitment of HIV-susceptible T cells and macrophages by MIP-1alpha, and 3) preventing the establishment and maintenance of infected macrophages as a reservoir for HIV.

Animals↗
PubMed1990

Localization in the rat spleen of carbon-laden macrophages introduced into the splenic artery: a subpopulation of macrophages entering the white pulp.

Heavily carbon-laden (HC) macrophages, largely derived from the red pulp of the donor spleen, were injected into the splenic artery of recipient rats. Immediately after injection, HC macrophages were found only in the marginal sinus and in the splenic cords. With time after injection, they appeared successively at the periphery of the white pulp, in the deeper white pulp, and finally in and near the germinal centers, suggesting migration of HC macrophages from the marginal sinus towards the germinal centers. The number of HC macrophages in and near the germinal centers reached a peak at 12 h. Most of the HC macrophages in the white pulp were spherical or ovoid in shape with a diameter of 7-11 microns in sections, having an eccentric round or oval nucleus often with a distinct nucleolus and a cap-like or horseshoe-like cytoplasm filled with carbon. When immunostained with monoclonal antibodies against rat macrophage subpopulations, more than 90% of HC macrophages in the white pulp were found to be ED1+2-3-. A population of the same type of macrophages, both in morphology and phenotype, were found in the red pulp of the donor spleen. They were different from the major residents, red pulp scavenger macrophages, which were ED1+2+3- and larger in size and irregular in shape. These results suggest the presence of a distinct subpopulation of macrophages which actively migrate into the splenic white pulp including the germinal centers. A discharge of transferred macrophages from the red pulp to the general circulation is also suggested.

Alkaline Phosphatase↗
PubMed1992

Macrophage development: III. Transformation of pulmonary macrophages from precursors in fetal lungs and their later maturation in organ culture.

The fate of macrophage precursors residing in 14-day prenatal rat lungs was followed in organ cultures to obtain a detailed, ultrastructurally resolved picture of the sequence and timing of events accompanying their transformation into typical pulmonary macrophages. Cultures were examined at close intervals during the first day (1, 2, 3, 4, 6, 9, 12, 15, 18, and 24 hr) and at wider intervals thereafter (2, 4, 5, 7, 9, and 13 days) to yield a developmental series of cells identified as in the macrophage line based on binding of peroxidase-coupled isolectin B4 of Griffonia simplicifolia (GSA I-B4) to cell membranes and on negligible content of peroxidase-positive granules in the cytoplasm. Organ culturing stimulated virtually all precursors to develop into macrophages. GSA-positive cells in explants occurred outside vessels in pulmonary connective tissue, and at the outset none were typical macrophages: 71% were angular cells, resembling unlabeled mesenchymal cells around them, 16% were undifferentiated leukocytes, and the remainder were irregularly shaped cells with few vacuoles intermediate between the preceding and the macrophages. During the first 12 hr in culture the proportion of angular cells and leukocytes fell to zero, and that of intermediate cells first rose, then receded. In the same interval the proportion of macrophages rose to 87.5%, and by 24 hr all GSA-positive cells were typical macrophages generally engorged with phagocytosed material; about 8 hr appear necessary for converting half the population. Notable ultrastructural changes during this period of transformation involved the centrioles and cytoskeleton, reflecting enhanced cell mobility and phagocytosis. A period of maturation followed, marked by disappearance of cellular debris from phagosomes and an increased prevalence of cells with elaborate lamellipodia. This accords with earlier work showing that macrophage Fc receptor density increases sharply during the first 24 hr, but elevated levels of histochemically demonstrable acid phosphatase appear only later. Mitotic activity was conspicuous in GSA-positive cells throughout both periods. 3H-thymidine labeling indices for precursors and macrophages, determined at six intervals between 1 hr and 24 hr, remained steady at approximately 34%, whereas indices of other categories of lung cells (GSA-negative stromal cells, pleural cells, and airway epithelium) began at this level but rapidly declined, indicating that the GSA-positive cells constitute a single population distinct from others in the lungs. Macrophages found outside the lung cultures after 4-5 days qualify as a mature population, but having migrated away from direct contact with the lung stroma, they survive only a week or two and no longer divide.

Animals↗
PubMed1981

Interaction between macrophages and aortic smooth muscle cells. Enhancement of cholesterol esterification in smooth muscle cells by media of macrophages incubated with acetylated LDL.

Mouse peritoneal macrophages were cultured for 24 h in Dulbecco-Vogt medium containing 10% calf serum. This medium was replaced with Dulbecco-Vogt medium containing 1% bovine serum albumin to which all subsequent additions were made. Medium changes, accompanied by appropriate additions, were made every 48 or 72 h and the media were used for incubation of aortic smooth muscle cells, prelabeled with [3H]cholesterol. The amount of labeled cholesteryl ester in the smooth muscle cells incubated for 48 h with macrophage media which had been collected 48-144 h after addition of acetylated LDL was increased 3-4 times above that present prior to postincubation. A marked increment in cholesteryl ester mass occurred also after incubation of smooth muscle cells with macrophage media conditioned with acetylated LDL and this effect was shared by maleylated LDL, but not by other negatively charged compounds. The increase in labeled cholesteryl ester in smooth muscle cells was more pronounced with media collected at later time intervals of incubation with macrophages and was evident 8 hr after postincubation. Only the d less than 1.063 fraction of the medium enhanced cholesterol esterification in smooth muscle cells. The acetylated LDL reisolated from macrophage media at d less than 1.063 did not compete with native LDL for degradation by smooth muscle cells. No increase in degradation of 125I-labeled acetylated LDL preincubated with macrophages was observed above that of non-preincubated acetylated LDL. The macrophage medium conditioned with acetylated LDL depressed [14C]acetate incorporation into sterols in smooth muscle cells and this effect was abolished by extraction of the medium with diethyl ether. The ratio of free to total cholesterol in the macrophage media collected after incubation with acetylated LDL increased from 28-70%, and a decrease occurred after incubation with smooth muscle cells. The enhancement of cholesterol esterification could be abolished by addition of high density apolipoprotein/sphingomyelin mixture during incubation with macrophages, even though excretion of free cholesterol into the medium increased 3-fold. It is proposed that when smooth muscle cells are presented with a lipoprotein in which an increase in the free to esterified cholesterol ratio occurred, and which is not recognized by a specific receptor, the enhancement of cellular cholesterol esterification is due mostly to a surface transfer of lipoprotein-free cholesterol. The present results offer another view of the possible interactions between macrophages and smooth muscle cells. A modified lipoprotein, not recognized by smooth muscle cells, is ingested by macrophages, which leads to accumulation of esterified cholesterol. Part of the esterified cholesterol undergoes hydrolysis and is excreted back into the medium, leading to enrichment of the lipoproteins in the medium with free cholesterol. This enrichment with free cholesterol promotes cholesterol esterification in smooth muscle cells.

Acylation↗
PubMed1986

Potential role of activated macrophages in acetaminophen hepatotoxicity. I. Isolation and characterization of activated macrophages from rat liver.

Twenty-four hours following treatment of rats with the analgesic acetaminophen (1.2 g/kg), we observed an infiltration of mononuclear cells into centrilobular regions of the liver in the absence of necrosis. To determine whether acetaminophen induces the accumulation and activation of mononuclear phagocytes, we compared the morphologic and functional characteristics of macrophages obtained from livers of acetaminophen-treated rats with those of resident macrophages (Kupffer cells) from untreated control animals. Macrophages were isolated from rat livers by combined collagenase/pronase perfusion, selective digestion, and differential centrifugation on a metrizamide gradient. Acetaminophen treatment resulted in a twofold increase in macrophage yields from the liver compared with controls. Macrophages isolated from treated animals were generally larger than resident Kupffer cells, were highly vacuolated, and adhered to culture dishes more rapidly. Liver macrophages from both treated and untreated rats phagocytized sheep red blood cells (sRBC) in a time-dependent manner, reaching a maximum after 60-75 min incubation with sRBCs. However, macrophages from livers of acetaminophen-treated rats phagocytized two to three times more sRBC than did resident Kupffer cells. Using the Boyden chamber technique, both macrophage populations were found to be chemotactic to a number of stimuli including the complement fragment, C5a, and synthetic collagenous peptides related to tissue breakdown products. Levels of migration of macrophages from livers of acetaminophen-treated rats were four to seven times greater than those of resident Kupffer cells. In addition, compared with resident Kupffer cells, macrophages from acetaminophen-treated rats released 30% more superoxide anion in response to the stimulus, 12-O-tetradecanoyl-phorbol-13-acetate. Taken together, these results suggest that acetaminophen treatment of rats leads to the recruitment and activation of macrophages in the liver.

Acetaminophen↗
PubMed1994

Mechanism of macrophage recognition of SH-oxidized erythrocytes: recognition of glycophorin A on erythrocytes by a macrophage receptor for sialosaccharides.

Mouse erythrocytes treated with diamide, an SH-oxidizing agent, attach to mouse resident peritoneal macrophages in the absence of serum. The mechanism by which macrophages recognize the SH-oxidized erythrocytes was investigated. Although phosphatidylserine-liposomes inhibited the macrophage recognition, there was no detectable phosphatidylserine on the outer surface of diamide-treated erythrocytes. It is unlikely that phosphatidylserine, that has been proposed to be a determinant in the recognition of some pathologic erythrocytes by macrophages, is involved in the recognition of diamide-treated erythrocytes. Sialyl lactose and glycophorin A effectively inhibited the macrophage recognition, while lactose and neuraminidase-treated glycophorin A did not. Disialoganglioside GD1a, but not monosialoganglioside GM1, partially inhibited the recognition. Trypsinized erythrocytes, in which majority of glycophorin A glycopeptides were expected to be removed from the cell surface, poorly attached to macrophages after diamide treatment. Therefore, it is likely that an interaction between glycophorin A on diamide-treated erythrocytes and a macrophage receptor for sialosaccharides is involved in the recognition. Similar inhibition specificity was observed in the macrophage recognition of erythrocytes treated with periodate, an oxidant that induces disulfide-dependent erythrocyte changes causing macrophage recognition, and of erythrocytes treated with SH-blocking agents, N-ethylmaleimide and p-chloromercuribenzoic acid, that were also found to be susceptible to macrophage recognition in the absence of serum. These results suggest that the macrophages recognize sialosaccharide chains of glycophorin A molecules on SH-oxidized or SH-blocked erythrocytes through a receptor for sialosaccharides.

Animals↗
PubMed1975

Studies of the macrophage complement receptor. Alteration of receptor function upon macrophage activation.

We have examined the roles of Fc receptors and complement receptors in mediating the interaction of sensitized sheep erythrocytes (E) with activated and with nonactivated mouse peritoneal macrophages. Both activated and nonactivated macrophages ingest IgG-coated erythrocytes [E(IgG)]; activated cells intest 1.5-2 times as man E(IgG) as do nonactivated macrophages. Thus, there is a quantitative difference in Fc receptor-mediated ingestion between activated and nonactivated macrophages. There is, however, a qualitative difference in function of complement receptors of activated and nonactivated macrophages. Nonactivated macrophages avidly bind complement-coated E [E(IgM)Ia1, but do not ingest them to a significant degree. Activated macrophages, on the other hand, bind and ingest E(IgM)C. The possibility of Fc receptor participation in mediating ingestion of E(IgM)C by activated macrophages was eliminated by blocking Fc receptors with an antimacrophage IgG fraction. Activated macrophages treated with antimacrophage IgG did not ingest E(igG) but did ingest both E(IgM)C AND E(IgM)C. Nonactivated macrophages treated with antimacrophage IgG did not interact at all with E(IgG). These cells bound, but did not ingest, E(IgM)C and E(IgM)C. Complement receptor-mediated ingestion is a marker for macrophage activation and may be physiologically important in the elimination of complement-coated particles.

Animals↗
PubMed1994

Macrophage suppression of granulocyte and macrophage growth following burn wound infection.

Burn injury results in alterations in granulocyte and macrophage production. Since macrophages may mediate these alterations we determined the effects of macrophages obtained from animals with burn injury with and without infection on the growth of marrow granulocyte macrophage progenitor cells (GM-CFCs). The in vitro GM-CFC growth response for maximally stimulated cultures was reduced by 25% to 30% (p < 0.01) for burned and infected (B + I) animal macrophages compared with burned (B) or sham (S) animals. Macrophages stimulated with endotoxin caused a further reduction for all groups in GM-CFC growth, most notably so for B + I macrophages. Burned + infected animal macrophages or all-endotoxin macrophages cocultured with indomethacin did not suppress GM-CFC growth. Following burn injury and infection, macrophages spontaneously elaborate negative regulators of myeloid growth that is further increased by endotoxin. It is likely that PGE2, a known negative regulator of granulocyte macrophage growth, is largely responsible for this suppressive effect.

Animals↗
PubMed1995

Recombinant human granulocyte colony-stimulating factor treatment improves macrophage suppression of granulocyte and macrophage growth after burn and burn wound infection.

Granulocyte and macrophage production after burn injury or burn wound infection is significantly reduced and further compromised by endotoxin (ET). Moreover, the macrophage seems to be the major source of this bone marrow suppression. We sought to determine if recombinant human granulocyte colony-stimulating factor (rhG-CSF), a hematopoietic growth factor that is capable of improving survival after experimental burn wound sepsis, altered postburn macrophage-mediated marrow suppression. Groups of male BDF1 mice (n = 6 to 10) receiving a 15% total body surface area burn +/- infection (B or B + I) with Pseudomonas aeruginosa were injected with 100 ng rhG-CSF twice daily. On day 3, peritoneal-elicited macrophages (5 x 10(6) cells/mL) from either rhG-CSF-treated or control (5% dextrose in water) mice were incubated +/- ET (300 ng/mL). The resultant macrophage supernatant was added to cultures of target marrow granulocyte-macrophage progenitor cells (GM-CFC) at a volume of 1:10. The GM-CFC growth as a percentage of cultures not containing macrophage supernatant were compared and reductions in the number of GM-CFC taken as an index of marrow suppression. Macrophages obtained from B and B + I animals reduced target GM-CFC growth, compared with macrophages from normal animals (B vs. normal animals p < 0.05). In addition, ET-stimulated macrophages induced further bone marrow suppression for all three groups (p < 0.01). Macrophages from granulocyte colony-stimulating factor-treated animals caused significantly less bone marrow suppression, compared with untreated animals for all groups (p < 0.05 to 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

IFN-gamma enhances bovine macrophage responsiveness to Mycobacterium bovis: Impact on bacterial replication, cytokine release and macrophage apoptosis.

We sought to determine the impact of bovine IFN-gamma on the interaction between Mycobacterium bovis and bovine macrophages. Bovine macrophages released small amounts of nitric oxide (NO), TNF-alpha, IL-1beta and IL-12 upon infection with bacille Calmette-Guérin (BCG). Prior pulsing of cells with IFN-gamma significantly enhanced the release of NO and IL-12. Infection of bovine macrophages with virulent M. bovis led to the release of higher levels of pro-inflammatory mediators, compared to levels released upon BCG infection. IFN-gamma treatment of macrophages enhanced the release of pro-inflammatory mediators, but did not modify bacterial replication in M. bovis-infected macrophages. Treatment of macrophages with a combination of IFN-gamma and LPS led to a reduction in bacterial replication. Infected cells treated with IFN-gamma/LPS progressed mostly through an apoptotic pathway, whereas untreated infected cells eventually died by necrosis. Agents that prevented the acquisition of bacteriostatic activity by activated macrophages also prevented the induction of apoptosis in infected macrophages (IL-10 and neutralizing anti-TNF-alpha). We conclude that virulent M. bovis is a major determinant of release of pro-inflammatory cytokines by macrophages. IFN-gamma amplifies the macrophage cytokine release in response to M. bovis. Induction of apoptosis is closely linked to the emergence of macrophage resistance to M. bovis replication, which is dependent on endogenous TNF-alpha release.

Animals↗
PubMed1981

Interactions between Histoplasma capsulatum and macrophages from normal and treated mice: comparison of the mycelial and yeast phases in alveolar and peritoneal macrophages.

Interactions between macrophages (alveolar and peritoneal) from normal, vaccinated (with heat-killed yeast cells), and Mycobacterium bovis BCG-treated mice and the mycelial and yeast phases of Histoplasma capsulatum were observed. Phagocytosis of microconidia, small hyphal fragments, and yeast cells occurred 4 to 6 h after the infection of macrophage cultures. Conversion to the yeast phase began at 6 to 7 h and was complete after a 72-h incubation at 37 degrees C. Macrophages surrounded and adhered to macroconidia and large hyphal elements. More macrophages (65 to 68%) from BCG-treated mice contained fungi at 24 h than did macrophages from normal or vaccinated mice. Although there was no increase in the number of fungi in macrophages from vaccinated mice, only the macrophages from BCG-treated mice contained fewer fungi after 48 h of infection with the mycelial phase of H. capsulatum. Fungal growth was not inhibited in any of the macrophage cultures when infected with the yeast phase. The macrophages infected with yeast cells were destroyed after 48 to 72 h in the culture. Only BCG-treated macrophages survived infection with the mycelial phase, whereas macrophages from normal and vaccinated mice were destroyed by the infection.

Animals↗
PubMed1997

Interaction of Yersinia enterocolitica with macrophages leads to macrophage cell death through apoptosis.

Suppression of the host defense is one of the hallmarks of Yersinia enterocolitica infection. This enteric pathogen resists phagocytosis and interferes with macrophage functions from an extracellular localization (oxidative-burst generation and tumor necrosis factor alpha production). In this study, we investigated the fate of the Y. enterocolitica-infected macrophage. We found that murine J774A.1 macrophages and macrophages derived from human monocytes were killed by infection with Y. enterocolitica. Analysis of cellular morphology and DNA fragmentation revealed that macrophage cell death occurs through the induction of apoptosis. A total of 92% +/- 5% (mean +/- standard deviation) of murine J774A.1 macrophages and 74% +/- 6% of human monocyte-derived macrophages underwent apoptosis upon Yersinia infection after 4 and 20 h, respectively. The broad-spectrum caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethylketone blocked completion of the Yersinia-induced apoptotic program but not the surface exposure of phosphatidylserine as an early-stage apoptotic event. Analysis of different Yersinia mutants showed that macrophage apoptosis depends on a functional Y. enterocolitica type III protein secretion system. Apoptotic cell death of macrophages was not related to the YopE-mediated cytotoxic effect of Yersinia, since disruption of actin microfilaments by a Y. enterocolitica strain expressing a restricted repertoire of yop genes, including YopE, did not result in macrophage apoptosis. Furthermore, Yersinia-induced cytotoxic alterations in epithelial HeLa cells, which are conferred by YopE, did not lead to apoptosis. Our data demonstrate for the first time that Y. enterocolitica promotes the apoptosis of macrophages, an effect which is clearly distinct from the morphological alterations mediated by Yersinia on epithelial HeLa cells.

Actins↗
PubMed2006

Macrophage ABCG1 deletion disrupts lipid homeostasis in alveolar macrophages and moderately influences atherosclerotic lesion development in LDL receptor-deficient mice.

OBJECTIVE: ABCG1 has recently been identified as a facilitator of cellular cholesterol and phospholipid efflux to high-density lipoprotein (HDL). Its expression in macrophages is induced during cholesterol uptake in macrophages and by liver X receptor (LXR). The role of macrophage ABCG1 in atherosclerotic lesion development is, however, still unknown. METHODS AND RESULTS: To assess the role of macrophage ABCG1 in atherosclerosis, we generated low-density lipoprotein (LDL) receptor knockout (LDLr-/-) mice that are selectively deficient in macrophage ABCG1 by using bone marrow transfer (ABCG1-/- --> LDLr-/-). Peritoneal macrophages isolated from donor ABCG1-/- mice exhibited a 22% (P=0.0007) decrease in cholesterol efflux to HDL. To induce atherosclerosis, transplanted mice were fed a high-cholesterol diet containing 0.25% cholesterol and 15% fat for 6 and 12 weeks. Serum lipid levels and lipoprotein profiles did not differ significantly between ABCG1-/- --> LDLr-/- mice and controls. In lungs of ABCG1-/- --> LDLr-/- mice a striking accumulation of lipids was observed in macrophages localized to the subpleural region. After 6 weeks of high-cholesterol diet feeding the atherosclerotic lesion size was 49+/-12x10(3) microm2 for ABCG1+/+ --> LDLr-/- mice versus 65+/-15x103 microm2 for ABCG1-/- --> LDLr-/- mice and after 12 weeks of high-cholesterol diet feeding 124+/-17x10(3) microm2 for ABCG1+/+ --> LDLr-/- mice versus 168+/-17x10(3) microm2 for ABCG1-/- --> LDLr-/- mice. Atherosclerotic lesion size depended on both time and the macrophage ABCG1 genotype (P=0.038 by 2-way ANOVA, n > or = 8), indicating a moderately 33% to 36% increase in lesion formation in the absence of macrophage ABCG1. CONCLUSIONS: Macrophage ABCG1 deficiency does lead to heavy lipid accumulation in macrophages of the lung, and also a moderately significant effect on atherosclerotic lesion development was observed.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed1983

Human alveolar macrophage support of lymphocyte responses to mitogens and antigens. Analysis and comparison with autologous peripheral-blood-derived monocytes and macrophages.

Observations from animal studies and investigations using human peripheral-blood-derived macrophages may not be representative of human alveolar macrophage functions. Thus, we extensively examined and compared accessory cell functions of autologous human alveolar macrophages and peripheral-blood-derived monocytes and macrophages obtained from healthy, nonsmoking volunteer subjects. The alveolar and peripheral-blood-derived cells differed in ability to enhance mitogen- and antigen-stimulated transformation responses of purified autologous lymphocytes. Peripheral-blood-derived cells supported greater lymphocyte responses to optimal concentrations of several mitogens, but alveolar macrophages supported much greater responses to suboptimal concentrations of the mitogen phytohemagglutinin. Peripheral-blood-derived macrophages supported, but alveolar macrophages did not support, lymphocyte responses to streptococcal and influenza virus antigens. Such relative accessory cell functions of the different macrophages and monocytes were not due to different kinetics of response, nor were they due to differences in the proportion of macrophages required to support the lymphocyte responses. These data indicate that human alveolar macrophages have functional characteristics different from autologous peripheral-blood-derived monocytes and macrophages. Such differences may be important in both pulmonary immune homeostasis and in the pathogenesis of pulmonary disease.

Adult↗
PubMed1987

Foam cell-forming J774 macrophages have markedly elevated acyl coenzyme A:cholesterol acyl transferase activity compared with mouse peritoneal macrophages in the presence of low density lipoprotein (LDL) despite similar LDL receptor activity.

Cholesteryl ester (CE) accumulation in arterial wall macrophages (foam cells) is a prominent feature of atherosclerotic lesions. We have previously shown that murine J774 macrophages, unlike mouse peritoneal macrophages, accumulate large amounts of CE from unmodified low density lipoprotein (LDL). We now report a direct comparison of acyl coenzyme A:cholesterol acyl transferase (ACAT) activity in J774 and mouse peritoneal macrophages. Despite similar chloroquine-inhibitable 125I-LDL degradation in the two macrophages, ACAT activity in LDL-treated J774 macrophages was 10-30-fold higher than that in LDL-treated mouse peritoneal macrophages. In contrast, acetyl-LDL (matched for degradation with LDL) caused marked stimulation of ACAT activity in mouse peritoneal macrophages. From these data we conclude that in the presence of LDL, J774 macrophages have a highly active ACAT cholesterol esterification pathway compared with mouse peritoneal macrophages; and in mouse peritoneal macrophages, there is a marked difference in the ability of acetyl-LDL vs. LDL to stimulate ACAT even when the lipoproteins are matched for degradation.

Animals↗