Decreased inflammatory response in Toll-like receptor 2 knockout mice is associated with exacerbated Pneumocystis pneumonia

Wang, Shao Hung; Zhang, Chen; Lasbury, Mark E.; Liao, Chung Ping; Durant, Pamela J.; Tschang, Dennis; Lee, Chao Hung

doi:10.1016/j.micinf.2007.12.014

Cited by 19 publications

(22 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We showed that early assembly of the NADPH oxidase is incomplete in TLR2-deficient PMN, but successful at later time-points. These findings are supported by previous studies showing that macrophages of TLR2 −/− mice are unable to produce superoxide and H 2 O 2 and impaired in p47 phox phosphorylation [29,43]. Furthermore, MyD88 −/− macrophages are inefficient to recruit p22 phox and p47 phox to bacteria-containing phagosomes [30].…”

Section: Discussionsupporting

confidence: 86%

TLR2 enhances NADPH oxidase activity and killing of Staphylococcus aureus by PMN

Jann¹,

Schmaler²,

Ferracin³

et al. 2011

Immunology Letters

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 86%

TLR2 enhances NADPH oxidase activity and killing of Staphylococcus aureus by PMN

Jann¹,

Schmaler²,

Ferracin³

et al. 2011

Immunology Letters

View full text Add to dashboard Cite

“…The expression levels of PU.1 and Dectin-1 genes in AMs were gradually decreased as PCP progressed, but the changes did not become statistically significant until the late stage of the disease (6 weeks). This is consistent with the chronic nature of this disease, as our previous study showed that Pneumocystis-infected mice started to lose body weight and show symptoms at approximately 6 weeks after initiation of infection (35).…”

Section: Myd88supporting

confidence: 90%

Downregulation of PU.1 Leads to Decreased Expression of Dectin-1 in Alveolar Macrophages during Pneumocystis Pneumonia

Zhang

Wang²,

Liao

et al. 2010

Infect Immun

Self Cite

View full text Add to dashboard Cite

Dectin-1 is an important macrophage phagocytic receptor recognizing fungal ␤-glucans. In this study, the mRNA levels of the Dectin-1 gene were found to be decreased by 61% in alveolar macrophages (AMs) from Pneumocystis-infected mice. The expression of Dectin-1 protein on the surface of these cells was also significantly decreased. By fluorescence in situ hybridization, mRNA expression levels of the transcription factor PU.1 were also found to be significantly reduced in AMs from Pneumocystis-infected mice. Electrophoretic mobility shift assay showed that PU.1 protein bound Dectin-1 gene promoter. With a luciferase reporter gene driven by the Dectin-1 gene promoter, the expression of the PU.1 gene in NIH 3T3 cells was found to enhance the luciferase activity in a dose-dependent manner. PU.1 expression knockdown by small interfering RNA (siRNA) caused a 63% decrease in Dectin-1 mRNA level and 40% decrease in protein level in AMs. Results of this study indicate that downregulation of PU

show abstract

“…Toll-like receptor 2 (TLR2) is an additional receptor expressed by alveolar macrophages that mediates CXCL2/MIP-2 production (54) and, in humans, interleukin-8 (IL-8) production in cooperation with the macrophage mannose receptor (39). P. murina infection in TLR2 Ϫ/Ϫ mice is prolonged and associated with a lack of inflammatory responsiveness (51). Other studies have implicated TLR4 in alveolar macrophage recognition of P. murina (6).…”

mentioning

confidence: 99%

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

Nelson

Metz

et al. 2009

Infect Immun

View full text Add to dashboard Cite

Src family tyrosine kinases (SFKs) phosphorylate immunotyrosine activation motifs in the cytoplasmic tail of multiple immunoreceptors, leading to the initiation of cellular effector functions, such as phagocytosis, reactive oxygen species production, and cytokine production. SFKs also play important roles in regulating these responses through the activation of immunotyrosine inhibitory motif-containing inhibitory receptors. As myeloid cells preferentially express the SFKs Hck, Fgr, and Lyn, we questioned the role of these kinases in innate immune responses to Pneumocystis murina. Increased phosphorylation of Hck was readily detectable in alveolar macrophages after stimulation with P. murina. We further observed decreased phosphorylation of Lyn on its C-terminal inhibitory tyrosine in P. murina-stimulated alveolar macrophages, indicating that SFKs were activated in alveolar macrophages in response to P. murina. Mice deficient in Hck, Fgr, and Lyn exhibited augmented clearance 3 and 7 days after intratracheal administration of P. murina, which correlated with elevated levels of interleukin 1␤ (IL-1␤), IL-6, CXCL1/KC, CCL2/monocyte chemoattractant protein 1, and granulocyte colony-stimulating factor in lung homogenates and a dramatic increase in macrophage and neutrophil recruitment. Augmented P. murina clearance was also observed in Lyn ؊/؊ mice 3 days postchallenge, although the level was less than that observed in Hck ؊/؊ Fgr ؊/؊ Lyn ؊/؊ mice. A correlate to augmented clearance of P. murina in Hck ؊/؊ Fgr ؊/؊ Lyn ؊/؊ mice was a greater ability of alveolar macrophages from these mice to kill P. murina in vitro, suggesting that SFKs regulate the alveolar macrophage effector function against P. murina. Mice deficient in paired immunoglobulin receptor B (PIR-B), an inhibitory receptor activated by SFKs, did not exhibit enhanced inflammatory responsiveness to or clearance of P. murina. Our results suggest that SFKs regulate innate lung responses to P. murina in a PIR-B-independent manner.Although the advent of prophylactic therapy against Pneumocystis jirovecii alone or in combination with highly active antiretroviral therapy has reduced the incidence of pneumonia caused by this fungal pathogen, this infection remains the most prevalent opportunistic infection in individuals with AIDS (25). Furthermore, individuals receiving immunosuppressive therapies, such as individuals undergoing solid organ or hematopoietic cell transplantation, are a growing population susceptible to Pneumocystis pneumonia (34) (33). These observations warrant a more thorough examination of interactions between Pneumocystis and the host in order to define and develop new vaccine and immunotherapeutic approaches to treat Pneumocystis pneumonia.An intense area of research over the last decade is investigating how lung immune cells recognize and respond to inhaled pathogens, such as P. murina. After inhalation of P. murina into the lungs, one of the first interactions with the host is recognition by the alveolar macrophage. Our laboratory has prev...

show abstract

Decreased inflammatory response in Toll-like receptor 2 knockout mice is associated with exacerbated Pneumocystis pneumonia

Cited by 19 publications

References 29 publications

TLR2 enhances NADPH oxidase activity and killing of Staphylococcus aureus by PMN

TLR2 enhances NADPH oxidase activity and killing of Staphylococcus aureus by PMN

Downregulation of PU.1 Leads to Decreased Expression of Dectin-1 in Alveolar Macrophages during Pneumocystis Pneumonia

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

Contact Info

Product

Resources

About