The role of alveolar macrophages in Pneumocystis carinii degradation and clearance from the lung.

Limper, Andrew H.; Hoyte, Jacques S.; Standing, Joseph E.

doi:10.1172/jci119384

Cited by 173 publications

(157 citation statements)

References 55 publications

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“…Alveolar macrophages (AMs) are critical components of the pulmonary innate immune response to infectious challenge and likely represent important effector cells in the host response to Pneumocystis (Limper et al, 1997;Steele et al, 2003). Human AMs express surface innate immune receptors such as mannose receptors (Greenberg and Grinstein, 2002) that can mediate Pneumocystis phagocytosis (Ezekowitz et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Cdc42 and RhoB Activation Are Required for Mannose Receptor-mediated Phagocytosis by Human Alveolar Macrophages

Zhang

Zhu

et al. 2005

MBoC

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Human alveolar macrophages (AMs) phagocytose Pneumocystis (Pc) organisms predominantly through mannose receptors, although the molecular mechanism mediating this opsonin-independent process is not known. In this study, using AMs from healthy individuals, Pc phagocytosis was associated with focal F-actin polymerization and Cdc42, Rac1, and Rho activation in a time-dependent manner. Phagocytosis was primarily dependent on Cdc42 and RhoB activation (as determined by AM transfection with Cdc42 and RhoB dominant-negative alleles) and mediated predominantly through mannose receptors (as determined by siRNA gene silencing of AM mannose receptors). Pc also promoted PAK-1 phosphorylation, which was also dependent on RhoGTPase activation. HIV infection of AMs (as a model for reduced mannose receptor expression and function) was associated with impaired F-actin polymerization, reduced Cdc42 and Rho activation, and markedly reduced PAK-1 phosphorylation in response to Pc organisms. In healthy AMs, Pc phagocytosis was partially dependent on PAK activation, but dependent on the Rho effector molecule ROCK. These data provide a molecular mechanism for AM mannose receptor-mediated phagocytosis of unopsonized Pc organisms that appears distinct from opsonin-dependent phagocytic receptors. Reduced AM mannose receptor-mediated Cdc42 and Rho activation in the context of HIV infection may represent a mechanism that contributes to the pathogenesis of opportunistic pneumonia.

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Section: Introductionmentioning

confidence: 99%

Cdc42 and RhoB Activation Are Required for Mannose Receptor-mediated Phagocytosis by Human Alveolar Macrophages

Zhang

Zhu

et al. 2005

MBoC

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“…It is widely reported that phagocytosis by alveolar macrophages (AMs) is the predominant mechanism of Pneumocystis murina clearance from the lungs (6)(7)(8); however, the mechanisms by which macrophages kill P. murina are not completely understood. It is hypothesized that on phagocytosis, the oxidative burst by macrophages, primarily the generation of hydrogen peroxide and superoxide, has a direct cytotoxic effect on P. murina (9,10).…”

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confidence: 99%

IL-33 And M2A Alveolar Macrophages Promote Lung Defense Against The Atypical Fungal Pathogen Pneumocystis Murina

Nelson

Christmann²,

Metz

et al. 2011

B14. Novel Treatments for Lung Infections: Modulating Immune Responses

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We have recently reported that mice deficient in the myeloid Src-family tyrosine kinases Hck, Fgr, and Lyn (Src triple knockout [TKO]) had augmented innate lung clearance of Pneumocystis murina that correlated with a higher ability of alveolar macrophages (AMs) from these mice to kill P. murina. In this article, we show that despite possessing enhanced killing, AMs from naive Src TKO mice did not demonstrate enhanced inflammatory responses to P. murina. We subsequently discovered that both AMs and lungs from P. murina-infected Src TKO mice expressed significantly greater levels of the M2a markers RELM-α and Arg1, and the M2a-associated chemokines CCL17 and CCL22 than did wild-type mice. IL-4 and IL-13, the primary cytokines that promote M2a polarization, were not differentially produced in the lungs between wild-type and Src TKO mice. P. murina infection in Src TKO mice resulted in enhanced lung production of the novel IL-1 family cytokine IL-33. Immunohistochemical analysis of IL-33 in lung tissue revealed localization predominantly in the nucleus of alveolar epithelial cells. We further demonstrate that experimental polarization of naive AMs to M2a resulted in more efficient killing of P. murina compared with untreated AMs, which was further enhanced by the addition of IL-33. Administration of IL-33 to C57BL/6 mice increased lung RELM-α and CCL17 levels, and enhanced clearance of P. murina, despite having no effect on the cellular composition of the lungs. Collectively, these results indicate that M2a AMs are potent effector cells against P. murina. Furthermore, enhancing M2a polarization may be an adjunctive therapy for the treatment of Pneumocystis. Pneumonia caused by NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptwere diagnosed in the year 2009, and 25,000 deaths (19,000 in 2002) were recorded as a result of HIV infection (2). Although the advent of highly active antiretroviral therapy (HAART) has decreased the overall incidence of Pneumocystis carinii pneumonia (3), the mortality rate of those requiring hospitalization remains high (3). A recent retrospective study in an academic medical center found that overall hospital mortality rate to P. jiroveci pneumonia was 11.6%, and in those patients requiring intensive care, 29.0% (4). An additional study summarized the experience with HIV-associated P. carinii pneumonia over a 21-y period in a single center and found that mortality was 10.1% for the period from 1985 through 1989, 16.9% for the period from 1990 through June 1996, and 9.7% for the period from July 1996 through 2006 (i.e., the HAART era) (5). A major concern voiced by this study is the similar mortality associated with P. jiroveci pneumonia pre-and post-HAART.It is widely reported that phagocytosis by alveolar macrophages (AMs) is the predominant mechanism of Pneumocystis murina clearance from the lungs (6-8); however, the mechanisms by which macrophages kill P. murina are not completely understood. It is hypothesized that on phagocytosis, the oxidative burst b...

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“…carinii trophozoites were isolated from infected lungs as described previously (8) and then labeled by incubating 4 ϫ 10 7 organisms in 2 ml of Dulbecco's minimum essential medium (DMEM) containing 250 Ci of ProMix reagent (Amersham Biosciences, Piscataway, N.J.) (containing a mixture of [ 35 S]methionine and [ 35 S]cysteine) for 18 h at 37°C with 5% CO 2 as described by Limper et al (21). Unincorporated label was removed from P. carinii by washing the organisms repeatedly in 500 l of DMEM containing 1 mg of bovine serum albumin (BSA) per ml until an insignificant amount of radioactivity was detected in the wash.…”

Section: Methodsmentioning

confidence: 99%

“…The importance of alveolar macrophages is shown by the demonstration that Pneumocystis organisms are not cleared in alveolar macrophage-depleted rats (21). In addition, administration of granulocyte-macrophage colony-stimulating factor, which has been shown to activate alveolar macrophages during Pneumocystis infection (30), decreases the severity of PcP (22).…”

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confidence: 99%

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Effect of the Transcription Factor GATA‐2 on Phagocytic Activity of Alveolar Macrophages from Pneumocystis carinii‐Infected Hosts

Lasbury

Tang

Durant

et al. 2001

J Eukaryotic Microbiology

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Experiments were performed to determine whether this defect is specific for P. carinii organisms. The results showed that these macrophages were unable to phagocytose both P. carinii organisms and fluorescein isothiocyanate (FITC)-conjugated latex beads, indicating that alveolar macrophages from P. carinii-infected hosts have a general defect in phagocytosis. To determine whether this defect correlates with the recently discovered down-regulation of the GATA-2 transcription factor gene during P. carinii infection, alveolar macrophages from dexamethasone-suppressed or healthy rats were treated with anti-GATA-2 oligonucleotides and then assayed for phagocytosis. Aliquots of the alveolar macrophages were also treated with the sense oligonucleotides as the control. Cells treated with the antisense oligonucleotides were found to have a 46% reduction in phagocytosis of P. carinii organisms and a 65% reduction in phagocytosis of FITC-latex beads compared to those treated with the sense oligonucleotides. To determine whether the defect in phagocytosis in alveolar macrophages from P. carinii-infected hosts can be corrected by overexpression of GATA-2, a plasmid containing the rat GATA-2 gene in the sense orientation driven by the cytomegalovirus (CMV) promoter was introduced into alveolar macrophages from P. carinii-infected rats. Aliquots of the same cells transfected with a plasmid containing GATA-2 in the antisense orientation relative to the CMV promoter served as the control. Alveolar macrophages treated with the sense GATA-2 expression construct were found to increase their phagocytic activity by 66% in phagocytosis of P. carinii organisms and by 280% in phagocytosis of FITC-latex beads compared to those that received the antisense GATA-2 construct. The results of this study indicate that GATA-2 plays an important role in the regulation of phagocytosis in alveolar macrophages during P. carinii infection.

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The role of alveolar macrophages in Pneumocystis carinii degradation and clearance from the lung.

Cited by 173 publications

References 55 publications

Cdc42 and RhoB Activation Are Required for Mannose Receptor-mediated Phagocytosis by Human Alveolar Macrophages

Cdc42 and RhoB Activation Are Required for Mannose Receptor-mediated Phagocytosis by Human Alveolar Macrophages

IL-33 And M2A Alveolar Macrophages Promote Lung Defense Against The Atypical Fungal Pathogen Pneumocystis Murina

Effect of the Transcription Factor GATA‐2 on Phagocytic Activity of Alveolar Macrophages from Pneumocystis carinii‐Infected Hosts

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