Role of Alveolar Macrophages in the Neutrophil-dependent Defense System against<i>Pseudomonas aeruginosa</i>Infection in the Lower Respiratory Tract: Amplifying Effect of Muramyl Dipeptide Analog

Ozaki, Toshio; Maeda, Michihiko; Hayashi, Hideki; Nakamura, Yoichi; Moriguchi, Hiroki; Kamei, Toshihiko; Yasuoka, Susumu; Ogura, Takeshi

doi:10.1164/ajrccm/140.6.1595

Cited by 23 publications

(15 citation statements)

References 7 publications

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“…Previous findings also indicate that lung epithelial cells may play a key role in the production of proinflammatory cytokines (25,26). Consistent with previous studies, we also found that activation of two signaling proteins (JNK and NF-B) was blunted in both TPRC1-silenced epithelial cells and TRPC1 Ϫ/Ϫ mice (38,39). Critically, we reveal a new mechanism by identifying that Ca 2ϩ entry via TRPC1 is essential for the activation.…”

Section: Discussionsupporting

confidence: 92%

Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase Cα Signaling

Zhou

Yan

Sun

et al. 2015

Molecular and Cellular Biology

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dTransient receptor potential channel 1 (TRPC1) is a nonselective cation channel that is required for Ca 2؉ homeostasis necessary for cellular functions. However, whether TRPC1 is involved in infectious disease remains unknown. Here, we report a novel function for TRPC1 in host defense against Gram-negative bacteria. TRPC1؊/؊ mice exhibited decreased survival, severe lung injury, and systemic bacterial dissemination upon infection. Furthermore, silencing of TRPC1 showed decreased Ca 2؉ entry, reduced proinflammatory cytokines, and lowered bacterial clearance. Importantly, TRPC1 functioned as an endogenous Ca 2؉ entry channel critical for proinflammatory cytokine production in both alveolar macrophages and epithelial cells. We further identified that bacterium-mediated activation of TRPC1 was dependent on Toll-like receptor 4 (TLR4), which induced endoplasmic reticulum (ER) store depletion. After activation of phospholipase C␥ (PLC-␥), TRPC1 mediated Ca 2؉ entry and triggered protein kinase C␣ (PKC␣) activity to facilitate nuclear translocation of NF-B/Jun N-terminal protein kinase (JNK) and augment the proinflammatory response, leading to tissue damage and eventually mortality. These findings reveal that TRPC1 is required for host defense against bacterial infections through the TLR4-TRPC1-PKC␣ signaling circuit. P seudomonas aeruginosa and Klebsiella pneumoniae are opportunistic Gram-negative bacteria that infect a broad range of individuals, particularly immunocompromised people, causing high morbidity and mortality. These bacteria are increasingly becoming resistant to almost all the conventional antibiotics and remain major health threats (1, 2). Better understanding of the mechanism of host-pathogen interaction may facilitate the development of novel approaches to treat these infections. A number of studies have thus far focused on the pathogenesis of P. aeruginosa and K. pneumoniae in airway infectious diseases and have identified some critical innate immunity regulators for early-stage host defense (3-5).Members of the transient receptor potential channel (TRPC) and Orai families have been suggested as mediators of Ca 2ϩ entry channels in nonexcitable cells (6). Activation of the phospholipase C (PLC) signaling pathway generates inositol trisphosphate (IP 3 ) and diacylglycerol (DAG), which initiates Ca 2ϩ release from the endoplasmic reticulum (ER) stores followed by the activation of Ca 2ϩ entry channels that increase cytosolic Ca 2ϩ levels (7, 8). Ca 2ϩ entry through receptor-mediated channels is essential for regulating cellular functions, and TRPC1, which functions as a nonselective cation channel in many cell types, has been shown to be important in Ca 2ϩ entry that is initiated by store depletion (7, 9). In particular, TRPC1 is reportedly associated with cell proliferation, cell migration, enzyme and fluid secretion, normal metabolism in various organ systems, and cancer metastasis (6, 10, 11). TRPC1 could also form a heteromultimer with Orai1 and stromal interaction molecule 1 (STIM1), which are e...

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Section: Discussionsupporting

confidence: 92%

Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase Cα Signaling

Zhou

Yan

Sun

et al. 2015

Molecular and Cellular Biology

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“…We found that the lungs of cav1 KO mice exhibit increases in proinflammatory cytokines, but a similar increase was not found in the BAL fluid of these mice. Thus, lung epithelial cells might also contribute to the production of cytokines (41,58,59), whereas macrophages and neutrophils are traditionally regarded as the main players in inflammatory responses (60). To further explore the dysregulation of inflammatory response in KO mice, modifications of the cell signaling pathway in the lungs were examined.…”

Section: Discussionmentioning

confidence: 99%

Elevated Inflammatory Response in Caveolin-1-deficient Mice with Pseudomonas aeruginosa Infection Is Mediated by STAT3 Protein and Nuclear Factor κB (NF-κB)

Yuan

Huang

Fox

et al. 2011

Journal of Biological Chemistry

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Caveolin-1 (Cav-1), an important composition protein within the flask-shaped membrane invaginations termed caveolae, may play a role in host defense against infections. However, the phenotype in Pseudomonas aeruginosa-infected cav1 knock-out (KO) mice is still unresolved, and the mechanism involved is almost entirely unknown. Using a respiratory infection model, we confirmed a crucial role played by Cav-1 in host defense against this pathogen because Cav-1 KO mice showed increased mortality, severe lung injury, and systemic dissemination as compared with wild-type (WT) littermates. In addition, cav1 KO mice exhibited elevated inflammatory cytokines (IL-6, TNF-␣, and IL-12a), decreased phagocytic ability of macrophages, and increased superoxide release in the lung, liver, and kidney. We further studied relevant cellular signaling processes and found that STAT3 and NF-B are markedly activated. Our data revealed that the Cav-1/STAT3/NF-B axis is responsible for a dysregulated cytokine response, which contributes to increased mortality and disease progression. Moreover, downregulating Cav-1 in cell culture with a dominant negative strategy demonstrated that STAT3 activation was essential for the translocation of NF-B into the nucleus, confirming the observations from cav1 KO mice. Collectively, our studies indicate that Cav-1 is critical for inflammatory responses regulating the STAT3/NF-B pathway and thereby impacting P. aeruginosa infection.Pseudomonas aeruginosa accounts for 25% of Gram-negative bacteria isolated from hospitals and is associated with high morbidity and mortality (1). P. aeruginosa frequently infects immunocompromised individuals, such as those affected by ventilator-associated infection, severe burns, and cancer (2). More than 80% of cystic fibrosis patients suffer severe P. aeruginosa infection (3). This bacterium becomes increasingly resistant to various antibiotics. Further understanding the mechanism of the host-pathogen interaction may result in effective approaches to preventing this infection. Thus, P. aeruginosa has been a focus of airway infectious diseases (1, 4 -6).Recent studies suggest that P. aeruginosa also invades the lung epithelial cells through lipid raft-mediated endocytosis (7-9), which is a possible reason why this bacterium develops such formidable resistance to antibiotics (10). The invasion process of P. aeruginosa may involve certain lipid raft-associated proteins, including the caveolin family of proteins (9). Using caveolin-1 (cav1) 3 KO mice, two recent studies investigated the role of Cav-1 during P. aeruginosa infection (11, 12); however, their observations were very different. Thus, the role of Cav-1 in this infection needs to be clearly characterized.Caveolins are a family of integral membrane proteins involved in caveola formation and receptor-dependent endocytosis (13-15). Cav-1 and -2 are co-expressed in various cells, such as endothelial cells, airway epithelial cells, and type I pneumocytes. Cav-1 is the major component of caveolae, flaskshaped plasma membran...

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“…In the uninfected or untreated lung, PMNs comprise a small proportion of cells in the lower respiratory tract and macrophages constitute 85 to 98% of cells (15,26,29). However, the number of PMNs increases in lungs challenged with P. aeruginosa by intratracheal inoculation (19).…”

Section: Discussionmentioning

confidence: 99%

Role of Pulmonary Alveolar Macrophages in Defense of the Lung againstPseudomonas aeruginosa

Cheung¹,

Halsey

Speert

2000

Infect Immun

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Alveolar macrophages (AM) provide one of the first lines of defense against microbial invasion in the lower airways. The role of AM in the clearance of Pseudomonas aeruginosa in mice after intrapulmonary challenge was evaluated. AM were depleted by intranasal administration of liposome-encapsulated dichloromethylene diphosphonate. At 24 h following the instillation of liposomes, a sublethal dose of P. aeruginosa was inoculated intranasally. Spleen, liver, and lung tissue was then evaluated for viable bacteria and for histopathology. AM depletion of 78 to 88% did not affect the survival rate of infected mice or clearance of P. aeruginosa from the spleen, liver, or lung, compared to the control group, but the mice's susceptibility to Klebsiella pneumoniae was greatly enhanced. The recruitment of neutrophils to the lung was also not affected. Freshly explanted AM were not competent to phagocytose unopsonized P. aeruginosa but were able to phagocytose zymosan particles. Further studies were conducted to assess the in situ phagocytic activities of AM. Three hours after the intranasal instillation of P. aeruginosa or other particles, bronchoalveolar lavage was performed. AM phagocytosis of zymosan particles and latex beads exceeded that of P. aeruginosa. Neutrophils were recruited to the lung in response to a high-dose bacterial challenge. These results suggest that AM do not play an important role in defense of the lung against P. aeruginosa.

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Role of Alveolar Macrophages in the Neutrophil-dependent Defense System againstPseudomonas aeruginosaInfection in the Lower Respiratory Tract: Amplifying Effect of Muramyl Dipeptide Analog

Cited by 23 publications

References 7 publications

Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase Cα Signaling

Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase Cα Signaling

Elevated Inflammatory Response in Caveolin-1-deficient Mice with Pseudomonas aeruginosa Infection Is Mediated by STAT3 Protein and Nuclear Factor κB (NF-κB)

Role of Pulmonary Alveolar Macrophages in Defense of the Lung againstPseudomonas aeruginosa

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