Intestinal intussusception (ISS) commonly causes intestinal obstruction in children. One mechanism that has been proposed to cause ISS is inflammation-induced alteration of intestinal motility. We investigated whether innate inflammatory factors or altered motility is required for induction of ISS by LPS. We compared rates of ISS among BALB/c and C57BL/6 mice, mice lacking lymphocytes or depleted of phagocytes, or mice with defects in the Toll-like receptor 4 (TLR4) signaling pathway following administration of LPS or the Ca 2+ analog MnCl 2 . At 6 or 2 h after administration of LPS or MnCl 2 , respectively, mice underwent image analysis to assess intestinal contraction rate or laparotomy to identify ISS. LPS-induced ISS (LPS-ISS) was observed in BALB/c mice, but not in C57BL/6 mice or any BALB/c mice with disruptions of TLR4 signaling. LPS-induced serum TNF-α, IL-6, and nitric oxide (NO) and intestinal NO levels were similar in BALB/c and C57BL/6 mice. The rate of LPS-ISS was significantly reduced in phagocyte-depleted, but not lymphocyte-deficient, mice. Intestinal contraction rates were reduced in LPS-ISS-susceptible BALB/c mice, but not in LPS-ISS-resistant C57BL/6 or TLR4 mutant mice, suggesting a role for reduced intestinal contraction rate in LPS-ISS susceptibility. This was tested with MnCl 2, a Ca 2+ antagonist that reduced intestinal contraction rates and induced ISS, irrespective of mouse strain. Therefore, LPS-ISS is initiated by innate immune signaling that requires TLR4 and phagocytes but may be independent of TNF-α, IL-6, and NO levels. Furthermore, alteration of intestinal motility, specifically, reduced intestinal contraction rate, is a key factor in the development of ISS.
A distinct CD8 + NKT cell population expressing TCR § / g or TCR + / ˇhas been identified in liver and thymus.We wondered whether cell adhesion molecules play a role in the homing of CD8 + NKT cells to the liver.The number of liver CD8 + NKT cells was markedly reduced in leukocyte function-associated antigen (LFA)-1 -/-mice compared with wild-type (WT) mice.The reduction was restricted to the liver only and no measurable alterations were found in other organs.In the liver of SCID mice reconstituted with thymocytes from LFA-1 -/-or WT mice, the number of donor-derived CD8 + NKT cells was comparable and the vast majority of these cells expressed TCR § / g .In a reciprocal radiation thymocyte reconstitution system with LFA-1 -/-and WT mice, LFA-1 expressed on liver cells other than CD8 + NKT cells appeared to be required for the homing of thymic CD8 + NKT cells to the liver.The accumulation of donor thymocyte-derived CD8 + NKT cells in the liver of SCID mice was severely impaired by in vivo depletion of NK cells, but not of Kupffer cells.These results not only indicate that thymus provides a source for CD8 + NKT cells expressing TCR § / g in the liver, but also suggest that LFA-1 expressed on NK cells is involved in the homing of thymic CD8 + NKT cells to the liver.
Metastasis to the liver is a common event in clinical oncology. Blood-borne tumor cells (TCs) arriving to the liver sinusoids run into a special vascular bed. The lining of liver sinusoids is shared by Kupffer cells (KCs) and endothelial cells. KCs, liver-fixed macrophages, are responsible for detection and removal of “non-self” particles. To investigate their role in arresting blood-borne TCs and controlling tumor growth, we injected a syngeneic colon carcinoma cell line into a mesenteric vein of two groups of rats; one group was without Kupffer cells and the other normal controls. We removed the liver of these animals at different time intervals and performed immunohistochemical analysis with monoclonal antibodies (MoAbs) against our tumor cell line, three macrophage subpopulations, natural killer cells, and B and T lymphocytes. Additionally, we showed in vitro spontaneous cytotoxicity of KCs against our tumor cell line. Results suggest that KCs play a relevant role in arresting circulating TCs at the liver sinusoid, although it is limited to a small number of malignant cells. They also seem to play a major role in clearing neoplastic cells from the liver parenchyma, in controlling tumor growth in the very early stages of metastatic development, and in modulating the host immune response to cancer cells.
Acinetobacter baumannii is an emerging bacterial pathogen that causes nosocomial pneumonia and other infections. Although it is recognized as an increasing threat to immunocompromised patients, the mechanism of host defense against A. baumannii infection remains poorly understood. In this study, we examined the potential role of macrophages in host defense against A. baumannii infection using in vitro macrophage culture and the mouse model of intranasal (i.n.) infection. Large numbers of A. baumannii were taken up by alveolar macrophages in vivo as early as 4 h after i.n. inoculation. By 24 h, the infection induced significant recruitment and activation (enhanced expression of CD80, CD86 and MHC-II) of macrophages into bronchoalveolar spaces. In vitro cell culture studies showed that A. baumannii were phagocytosed by J774A.1 (J774) macrophage-like cells within 10 minutes of co-incubation, and this uptake was microfilament- and microtubule-dependent. Moreover, the viability of phagocytosed bacteria dropped significantly between 24 and 48 h after co-incubation. Infection of J774 cells by A. baumannii resulted in the production of large amounts of proinflammatory cytokines and chemokines, and moderate amounts of nitric oxide (NO). Prior treatment of J774 cells with NO inhibitors significantly suppressed their bactericidal efficacy (P<0.05). Most importantly, in vivo depletion of alveolar macrophages significantly enhanced the susceptibility of mice to i.n. A. baumannii challenge (P<0.01). These results indicate that macrophages may play an important role in early host defense against A. baumannii infection through the efficient phagocytosis and killing of A. baumannii to limit initial pathogen replication and the secretion of proinflammatory cytokines and chemokines for the rapid recruitment of other innate immune cells such as neutrophils.
Macrophages such as Kupffer cells in the liver are phagocytic delivery and accumulation of the bisphosmultifunctional cells.They are involved in host defense phonate clodronate. 2 The mechanism of the approach mechanisms and have a regulatory role in many biomedis explained as follows (for a recent review, see Van ical processes.Their selective depletion, using liposome-Rooijen and Sanders 3 ): encapsulated drugs, forms a widely accepted approach 1.The natural fate of liposomes is phagocytosis.to studying their functional aspects in vivo.We have 2. Once ingested by macrophages, the phospholipid compared the Kupffer cell-depleting activities of lipobilayers of the liposomes are disrupted under the influsome-encapsulated clodronate, propamidine, and ethylence of lysosomal phospholipases.enediaminetetraacetic acid (EDTA) for this purpose.3. Clodronate, intracellularly released in this way, These molecules represent the drug families of bisphosdoes not easily escape from the cell by crossing the cell phonates, diamidines (or aromatic polyamidines), and polyaminopolycarboxylic acid-chelating agents, respec-membranes.tively.The Kupffer cell-depleting activity of the lipo-4.As a result, the released clodronate accumulates some-encapsulated antimicrobial drug propamidine exin the cell.ceeded that of clodronate by about a factor of 10.EDTA 5.At a certain intracellular clodronate concentraappeared to be inefficacious for depletion of Kupffer tion, irreversible damage causes the macrophage to be cells in the rat.(HEPATOLOGY 1996;23:1239-1243.)killed.6. Clodronate, released in the circulation from dead From an evolutionary point of view, macrophages macrophages or by leakage from liposomes, will not form an ancient cell population, representing the main cross cell membranes and has an extremely short halfhost defense mechanism until the development of the life in circulation and body fluids, 4 explaining the fact immune system.During evolution, macrophages also that nonphagocytic cells are not affected.acquired an important role in the regulation of immune Macrophage depletion has been confirmed by immureactions and in controlling cell functions of various nocytochemical 2 and electronmicroscopical 5 methods nonphagocytic cells, in addition to their scavenger funcand by functional assays. 2 Using this approach, the tion.As a consequence, in mammals, macrophages are multifunctional role of macrophages in mammals has multifunctional cells. 1 been confirmed.Selective in vivo depletion of macrophages is a widely Kupffer cells, the resident macrophages in the liver, accepted approach to investigating whether macroare highly sensitive to intravenously injected clodrophages are involved in any particular biomedical connate liposomes.Using the liposome-mediated macrotrol mechanism.Because the effects of the usual methphage ''suicide'' approach, it has been shown that Kupfods for macrophage depletion, such as treatment with fer cells are able to suppress, for instance, the silica, carrageenan, and antimacrophage antibodies, development of the extra-erythrocytic stages of Plasmowere neither selective nor complete, we developed a dium berghei 6 and the growth of (metastatic) tumor new approach, based on the liposome-mediated intracells in the liver. 7It was also shown that Kupffer cells are crucial for the functional differentiation of liverspecific natural killer cells. 8The influence of Kupffer Abbreviations: EDTA, ethylenediaminetetraacetic acid; PBS, phosphate-cells on various processes in the liver might well be buffered saline.mediated by their production and secretion of cyto-
SGN-40 is a therapeutic antibody targeting CD40, which induces potent anti-lymphoma activities via direct apoptotic signalling cells and by cell-mediated cytotoxicity. Here we show antibody-dependent cellular phagocytosis (ADCP) by macrophages to contribute significantly to the therapeutic activities and that the antitumour effects of SGN-40 depend on Fc interactions.
Moderate exercise training is associated with a decreased risk for upper respiratory tract infection in human and animal studies, but the mechanisms have not been elucidated. Lung macrophages play an important role in resistance to respiratory infection, and moderate exercise can enhance macrophage antiviral resistance, but no studies have directly tested the role of lung macrophages in this response. This study tested the effect of lung macrophage depletion on susceptibility to infection following short-term moderate exercise training. Mice were assigned to one of four groups: exercise (Ex) and resting controls (Con) with and without clodronate encapsulated liposomes (CL(2)MDP-lip). Ex mice ran for 1 h on a treadmill for 6 days at 36 m/min, 8% grade. Fifteen minutes following exercise or rest on the last day of training, mice were intranasally inoculated with a standardized dose of herpes simplex virus type 1. Clodronate (Ex-CL(2)MDP-lip and Con-CL(2)MDP-lip) or PBS liposomes (Ex-PBS-lip and Con-PBS-lip) (100 microl) were intranasally administered following exercise or rest on the 4th day of training and again on the 4th day postinfection. Morbidity, mortality, and symptom severity were monitored for 21 days. Exercise decreased morbidity by 36%, mortality by 61%, and symptom severity score on days 5-7 (P < 0.05). Depletion of lung macrophages negated the beneficial effects of moderate exercise. This was indicated by no differences between Ex-CL(2)MDP-lip and Con-PBS-lip in morbidity (89 vs. 95%), mortality (79 vs. 95%), or symptom severity. Results indicate that lung macrophages play an important role in mediating the beneficial effects of moderate exercise on susceptibility to respiratory infection.
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