Activation of Macrophages to Kill Rickettsiae and Leishmania: Dissociation of Intracellular Microbicidal Activities and Extracellular Destruction of Neoplastic and Helminth Targets

Nacy, Carol A.; Oster, Charles N.; James, Stephanie; Meltzer, Monte S.

doi:10.1007/978-1-4757-1445-6_8

Cited by 21 publications

(22 citation statements)

References 48 publications

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“…As an additional note of caution, it should be mentioned that all the studies described here were carried out with thioglycollate-elicited macrophages because of the difficulty in conveniently obtaining the numbers of resident peritoneal macrophages required for biochemical analyses. Differences between the responses of thioglycollate-elicited peritoneal macrophages and the responses of resident peritoneal macrophages have been documented (14,19,35), and this fact needs to be kept in mind when our findings are interpreted.…”

Section: Discussionmentioning

confidence: 82%

Role of Toll-Like Receptor 4 in Macrophage Activation and Tolerance duringSalmonella entericaSerovar Typhimurium Infection

Cherayil

2003

Infect Immun

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Toll-like receptors (TLRs) play an important role in the innate immune response, particularly in the initial interaction between the infecting microorganism and phagocytic cells, such as macrophages. We investigated the role of TLR4 during infection of primary murine peritoneal macrophages with Salmonella enterica serovar Typhimurium. We found that macrophages from the C3H/HeJ mouse strain, which carries a functionally inactive Tlr4 gene, exhibit marked impairment of tumor necrosis factor alpha (TNF-␣) secretion in response to S. enterica serovar Typhimurium infection. However, activation of extracellular growth factor-regulated kinase and NF-B signaling pathways was relatively unaffected, as was increased expression of TNF-␣ mRNA. Furthermore, macrophage tolerance, which is associated with increased expression of the NF-B p50 and p52 subunits, was induced by S. enterica serovar Typhimurium even in the absence of functional TLR4. These results indicate that during infection of macrophages by S. enterica serovar Typhimurium, TLR4 signals are required at a posttranscriptional step to maximize secretion of TNF-␣. Signals delivered by pattern recognition receptors other than TLR4 are sufficient for the increased expression of the TNF-␣ transcript and at least some genes associated with macrophage tolerance.

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Section: Discussionmentioning

confidence: 82%

Role of Toll-Like Receptor 4 in Macrophage Activation and Tolerance duringSalmonella entericaSerovar Typhimurium Infection

Cherayil

2003

Infect Immun

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“…19,20 Consequently, the cellular activity and intracellular degradation processes for these macrophages may have varied significantly from the activity of macrophages under normal in vivo conditions. Hence, the second part of the study involved monitoring the intracellular degradation and processing of Texas red dextran-loaded PLGA microspheres in vivo over 7 days using CLSM.…”

Section: Resultsmentioning

confidence: 99%

Cytoplasmic delivery of a macromolecular fluorescent probe by poly(d,l-lactic-co-glycolic acid) microspheres

Newman

Kwon

Miller

et al. 2000

J. Biomed. Mater. Res.

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A macromolecular fluorescent probe encapsulated in poly(d, l-lactic-co-glycolic acid) (PLGA) microspheres was used as a model for studying cytoplasmic delivery of antigens. We hypothesized that Texas red dextran loaded in PLGA microspheres would be delivered to the cytoplasm and that cytoplasmic delivery would be affected by polymer molecular weight. Cellular localization of the Texas red dextran was investigated at two different molecular weights of PLGA: 6000 and 60,000 g/mol. Intracellular degradation and processing of Texas red dextran-loaded PLGA microspheres by mouse peritoneal macrophages was monitored both in vitro and in vivo for a 7-day period using confocal laser scanning microscopy (CLSM). The results revealed cytoplasmic delivery of the fluorescent probe at both molecular weights of PLGA. Furthermore, the CLSM images showed that both in vitro and in vivo, the kinetics of microsphere degradation and cytoplasmic delivery were more rapid for the 6000 g/mol PLGA microspheres than the 60,000 g/mol PLGA microspheres. Hence, this study provides physical evidence that PLGA microspheres are capable of cytoplasmic delivery and that delivery to the cytosol can be controlled by modifying formulation parameters such as polymer molecular weight.

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“…Thus, we and others have employed LPS as a potent in vitro triggering or "second" signal to induce IFN-y-primed MQ, to kill either extracellular tumor target cells [l, 21 or intracellular pathogens including Leishmania [2,3]. More recently, several investigations have suggested that TNF-a is a relevant physiological second signal for the induction of M a leishmanicidal activity [4-71. TNF-a produced by monocytes and M a and the closely related T lymphocyte product lymphotoxin are capable of inducing MQ, oxidative metabolism [8,91, c-fos and TNF-a mRNA expression [lo] and PGE;!…”

Section: Introductionmentioning

confidence: 99%

Phagocytosis enhances murine macrophage activation by interferon‐γ and tumor necrosis factor‐α

Corradin¹,

Buchmüller-Rouiller²,

Mauël³

1991

Eur J Immunol

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Previously, we reported that exposure of bone marrow-derived macrophages (M phi) to a phagocytic stimulus in the simultaneous presence of interferon-gamma (IFN-gamma) induced these cells to generate nitrite (NO2-). This effect was achieved using both living (i.e. promastigotes of the protozoan parasite Leishmania enriettii) and inert (latex beads) particles. When the phagocytic stimulus was Leishmania, enhanced intracellular killing accompanied elevated NO2- secretion. As shown here, the capacity of phagocytosis to elicit NO2- production by IFN-gamma-treated M phi was inhibited by antibody to murine recombinant tumor necrosis factor-alpha (rTNF-alpha), suggesting that phagocytosis enabled IFN-gamma to activate M phi via the induction of TNF-alpha as an autocrine second signal. M phi NO2- production in response to rIFN-gamma and either exogenous TNF-alpha or Leishmania was strongly enhanced by prostaglandin E2, consistent with such a mechanism. However, addition of either Leishmania promastigotes or latex beads to M phi cultures simultaneously exposed to both IFN-gamma and exogenous murine or human rTNF-alpha further potentiated activation as measured by NO2- release. Furthermore, anti-TNF antibody failed to inhibit M phi responses to rIFN-gamma and bacterial lipopolysaccharide (LPS) in the presence or absence of Leishmania; also exogenous rTNF-alpha did not significantly affect NO2- production by IFN-gamma/LPS cultures despite a strong enhancement by Leishmania. These results suggest that phagocytosis enhances M phi responses by a process more complex than the sole induction of TNF-alpha. Phagocytosis also increased M phi NO2- production elicited by IFN-gamma plus TNF-alpha in L-arginine-deficient media. These results indicate that phagocytosis may be an important mechanism of up-regulating M phi microbicidal activity, and could be particularly relevant upon arginine depletion which occurs during an inflammatory response.

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Activation of Macrophages to Kill Rickettsiae and Leishmania: Dissociation of Intracellular Microbicidal Activities and Extracellular Destruction of Neoplastic and Helminth Targets

Cited by 21 publications

References 48 publications

Role of Toll-Like Receptor 4 in Macrophage Activation and Tolerance duringSalmonella entericaSerovar Typhimurium Infection

Role of Toll-Like Receptor 4 in Macrophage Activation and Tolerance duringSalmonella entericaSerovar Typhimurium Infection

Cytoplasmic delivery of a macromolecular fluorescent probe by poly(d,l-lactic-co-glycolic acid) microspheres

Phagocytosis enhances murine macrophage activation by interferon‐γ and tumor necrosis factor‐α

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