The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses to<i>Pneumocystis murina</i>

Nelson, Michael Paul; Metz, Allison E.; Li, Shaoguang; Lowell, Clifford A.; Steele, Chad

doi:10.1128/iai.01441-08

Cited by 20 publications

(42 citation statements)

References 57 publications

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“…We have previously reported that mice deficient in the myeloid Src family kinases Hck, Fgr, and Lyn (Src TKO mice) demonstrated an increase in alternatively activated macrophages (28), which we have demonstrated to have an enhanced capacity to kill P. murina (28,29). Because Src TKO mice are more resistant to P. murina lung infection (29), we questioned whether this observation correlated with Mmp12 expression.…”

Section: P Murina Lung Exposure Results In the Induction Of Mmp12mentioning

confidence: 82%

ExperimentalPneumocystislung infection promotes M2a alveolar macrophage-derived MMP12 production

Nelson

Christmann

Dunaway

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Among several bacterial and viral pathogens, the atypical fungal organism Pneumocystis jirovecii has been implicated as a contributor to the pathogenesis of chronic obstructive pulmonary disease (COPD). In a previous study, we reported that Pneumocystis-colonized HIV-positive subjects had worse obstruction of airways and higher sputum levels of macrophage elastase/matrix metalloproteinase 12 (MMP12), a protease strongly associated with the development of COPD. Here, we examined parameters of Pneumocystis-induced MMP12 in the lungs of mice and its role in the lung immune response to murine Pneumocystis. Initial studies demonstrated that P. murina exposure induced Mmp12 mRNA expression in whole lungs and alveolar macrophages (AMs), which was dependent on the presence of CD4+ T cells as well as signal transducer and activator of transcription 6. Mmp12 mRNA expression was upregulated in AMs by interleukin (IL)-4 treatment, but downregulated by interferon (IFN)-γ, indicating preferential expression in alternatively activated (M2a) macrophages. IL-4 treatment induced the 54-kDa proenzyme form of MMP12 and the 22-kDa fully processed and active form, whereas IFN-γ failed to induce either. Despite a reported antimicrobial role in macrophage phagolysosomes, mice deficient in MMP12 were not found to be more susceptible to lung infection with P. murina. Collectively, our data indicate that MMP12 induction is a component of the P. murina-induced M2 response and thus provides insight into the link between Pneumocystis colonization/infection and exacerbations in COPD.

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Section: P Murina Lung Exposure Results In the Induction Of Mmp12mentioning

confidence: 82%

ExperimentalPneumocystislung infection promotes M2a alveolar macrophage-derived MMP12 production

Nelson

Christmann

Dunaway

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Unexpectedly, however, mice triple deficient in the SFKs Hck, Fgr, and Lyn (Src TKO mice) had augmented innate lung clearance of P. murina that correlated with both an increased lung inflammatory response and a greater ability of Src TKO AMs to kill P. murina in vitro (27). Because AMs are critical effector cells required for P. murina lung clearance (7), and because Src TKO AMs killed P. murina more efficiently (27), we hypothesized that Src TKO AMs would be hyperresponsive to P. murina stimulation resulting in increased inflammatory mediator production. Surprisingly, the opposite was true, as Src TKO AMs produced lower amounts of multiple mediators known to be produced by AMs in response to P. murina, including G-CSF, IL-1β, and IL-6.…”

Section: Discussionmentioning

confidence: 99%

“…RELM-α is a cysteine-rich secreted protein originally identified in the lung (44) and subsequently observed to be expressed by macrophages, eosinophils, epithelial cells, and endothelial cells (44,45). RELM-α stimulates production of MCP-1 (46) and IL-6 (46), both of which we have previously reported to be increased in the lungs of P. murina-infected Src TKO mice (27). RELM-α can also bind to F4/80 + cells (45), which we also reported to be recruited in greater numbers to the lungs of P. murina-infected Src TKO mice (27).…”

Section: Discussionmentioning

confidence: 99%

“…RELM-α stimulates production of MCP-1 (46) and IL-6 (46), both of which we have previously reported to be increased in the lungs of P. murina-infected Src TKO mice (27). RELM-α can also bind to F4/80 + cells (45), which we also reported to be recruited in greater numbers to the lungs of P. murina-infected Src TKO mice (27). Although RELM-α is considered a product of Th2 activation, models of Nippostrongylus brasiliensis GI infection (47) and Schistosoma mansoni lung infection (45) in RELM-α-deficient mice define a paradoxical role for RELM-α in suppressing Th2 responses.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous work, we found that mice deficient in the SFKs Hck, Fgr, and Lyn (Src TKO mice) had augmented innate lung clearance of P. murina (27). At 3 and 7 d postchallenge, Src TKO mice displayed increased levels of IL-1β, IL-6, G-CSF, CXCL1/KC, and CCL2/ MCP-1 (27).…”

Section: Lack Of a Heightened Inflammatory Response To P Murina By Smentioning

confidence: 99%

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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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c‐Src function is necessary and sufficient for triggering microglial cell activation

Socodato

Portugal

Domith

et al. 2014

Glia

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Microglial cells are the resident macrophages of the central nervous system. Their function is essential for neuronal tissue homeostasis. After inflammatory stimuli, microglial cells become activated changing from a resting and highly ramified cell shape to an amoeboid-like morphology. These morphological changes are associated with the release of proinflammatory cytokines and glutamate, as well as with high phagocytic activity. The acquisition of such phenotype has been associated with activation of cytoplasmic tyrosine kinases, including those of the Src family (SFKs). In this study, using both in vivo and in vitro inflammation models coupled to FRET-based time-lapse microscopy, lentiviruses-mediated shRNA delivery and genetic gain-of-function experiments, we demonstrate that among SFKs c-Src function is necessary and sufficient for triggering microglia proinflammatory signature, glutamate release, microglia-induced neuronal loss, and phagocytosis. c-Src inhibition in retinal neuroinflammation experimental paradigms consisting of intravitreal injection of LPS or ischemia-reperfusion injury significantly reduced microglia activation changing their morphology to a more resting phenotype and prevented neuronal apoptosis. Our data demonstrate an essential role for c-Src in microglial cell activation.

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The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses toPneumocystis murina

Cited by 20 publications

References 57 publications

ExperimentalPneumocystislung infection promotes M2a alveolar macrophage-derived MMP12 production

ExperimentalPneumocystislung infection promotes M2a alveolar macrophage-derived MMP12 production

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

c‐Src function is necessary and sufficient for triggering microglial cell activation

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