scholarly journals TREM-1 Amplifies Corneal Inflammation after Pseudomonas aeruginosa Infection by Modulating Toll-Like Receptor Signaling and Th1/Th2-Type Immune Responses

2011 ◽  
Vol 79 (7) ◽  
pp. 2709-2716 ◽  
Author(s):  
Minhao Wu ◽  
Anping Peng ◽  
Mingxia Sun ◽  
Qiuchan Deng ◽  
Linda D. Hazlett ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inflammatory Responses ◽  
Neutrophil Infiltration ◽  
Polymorphonuclear Neutrophil ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Content Type ◽  
Surface Receptors ◽  
Pseudomonas Aeruginosa Infection ◽  
And Function

ABSTRACTAs a novel family of cell surface receptors, triggering receptors expressed on myeloid cells (TREMs) play an important role in inflammatory responses. However, the role of TREMs in the ocular immune system remains unknown. In this study, we examined the expression and function of TREM-1 inPseudomonas aeruginosakeratitis, one of the most common sight-threatening ocular diseases. TREM-1 was significantly increased in human corneas afterP. aeruginosainfection. Consistent with TREM-1 expression at the human ocular surface, TREM-1 levels (mRNA and protein) were also elevated in the infected corneas of C57BL/6 (B6) mice at 1, 3, and 5 days postinfection. To determine whether TREM-1 dictates the outcome ofP. aeruginosakeratitis in susceptible mice, TREM-1 signaling in B6 mice was blocked with a soluble mTREM-1/Fc fusion protein. The results indicated that blockade of TREM-1 reduced the severity of corneal disease, polymorphonuclear neutrophil infiltration, Th1/proinflammatory cytokine expression and Toll-like receptor (TLR) activation but enhanced the production of Th2 cytokines, murine β-defensin 2 (mBD2), single Ig interleukin-1R-related molecule (SIGIRR), and ST2. Furthermore, we also used agonistic anti-mTREM-1 antibody to activate TREM-1 signaling in B6 mice and found that TREM-1 activation resulted in worsened disease and earlier corneal perforation in infected B6 mouse corneas and elevated production of proinflammatory cytokines and TLR signaling molecules but reduced expression of mBD2, SIGIRR, and ST2. To the best of our knowledge, this study provides the first evidence that TREM-1 functions as an inflammatory amplifier inP. aeruginosakeratitis by modulating TLR signaling and Th1/Th2 responses.

scholarly journals Acidosis Potentiates the Host Proinflammatory Interleukin-1β Response to Pseudomonas aeruginosa Infection

2014 ◽  
Vol 82 (11) ◽  
pp. 4689-4697 ◽  
Author(s):  
Iviana M. Torres ◽  
Yash R. Patankar ◽  
Tamer B. Shabaneh ◽  
Emily Dolben ◽  
Deborah A. Hogan ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Interleukin 1Β ◽  
Acidic Environment ◽  
Content Type ◽  
Inflammatory Damage ◽  
Pseudomonas Aeruginosa Infection ◽  
Peritonitis Model

ABSTRACTInfection byPseudomonas aeruginosa, and bacteria in general, frequently promotes acidification of the local microenvironment, and this is reinforced by pulmonary exertion and exacerbation. However, the consequence of an acidic environment on the host inflammatory response toP. aeruginosainfection is poorly understood. Here we report that the pivotal cellular and host proinflammatory interleukin-1β (IL-1β) response, which enables host clearance of the infection but can produce collateral inflammatory damage, is increased in response toP. aeruginosainfection within an acidic environment. Synergistic mechanisms that promote increased IL-1β release in response toP. aeruginosainfection in an acidic environment are increased pro-IL-1β induction and increased caspase-1 activity, the latter being dependent upon a functional type III secretion system of the bacteria and the NLRC4 inflammasome of the host. Using anin vivoperitonitis model, we have validated that the IL-1β inflammatory response is increased in mice in response toP. aeruginosainfection within an acidic microenvironment. These data reveal novel insights into the regulation and exacerbation of inflammatory responses toP. aeruginosa.

scholarly journals Pseudomonas aeruginosa Outer Membrane Vesicles Modulate Host Immune Responses by Targeting the Toll-Like Receptor 4 Signaling Pathway

2013 ◽  
Vol 81 (12) ◽  
pp. 4509-4518 ◽  
Author(s):  
Kelei Zhao ◽  
Xin Deng ◽  
Chuan He ◽  
Bisong Yue ◽  
Min Wu
Keyword(s):  
Immune Response ◽  
Pseudomonas Aeruginosa ◽  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Strain Pao1 ◽  
Content Type

ABSTRACTBacteria can naturally secrete outer membrane vesicles (OMVs) as pathogenic factors, while these vesicles may also serve as immunologic regulators if appropriately prepared. However, it is largely unknown whetherPseudomonas aeruginosaOMVs can activate inflammatory responses and whether immunization with OMVs can provide immune protection against subsequent infection. We purified and identified OMVs, which were then used to infect lung epithelial cellsin vitroas well as C57BL/6J mice to investigate the immune response and the underlying signaling pathway. The results showed that OMVs generated fromP. aeruginosawild-type strain PAO1 were more cytotoxic to alveolar epithelial cells than those from quorum-sensing (QS)-deficient strain PAO1-ΔlasR. The levels of Toll-like receptor 4 (TLR4) and proinflammatory cytokines, including interleukin-1β (IL-1β) and IL-6, increased following OMV infection. Compared with lipopolysaccharide (LPS), lysed OMVs in which the membrane structures were broken induced a weak immune response. Furthermore, expression levels of TLR4-mediated responders (i.e., cytokines) were markedly downregulated by the TLR4 inhibitor E5564. Active immunization with OMVs or passive transfer of sera with a high cytokine quantity acquired from OMV-immunized mice could protect healthy mice against subsequent lethal PAO1 challenges (1.5 × 1011CFU). Collectively, these findings indicate that naturally secretedP. aeruginosaOMVs may trigger significant inflammatory responses via the TLR4 signaling pathway and protect mice against pseudomonal lung infection.

scholarly journals Lysosomal trafficking regulator Lyst links membrane trafficking to toll-like receptor–mediated inflammatory responses

2016 ◽  
Vol 214 (1) ◽  
pp. 227-244 ◽  
Author(s):  
Andreas Westphal ◽  
Weijia Cheng ◽  
Jinbo Yu ◽  
Guntram Grassl ◽  
Martina Krautkrämer ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Membrane Trafficking ◽  
Inflammatory Responses ◽  
Functional Integration ◽  
Receptor Signaling ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Lysosomal Trafficking ◽  
Phagosomal Maturation ◽  
Chediak Higashi Syndrome

Subcellular compartmentalization of receptor signaling is an emerging principle in innate immunity. However, the functional integration of receptor signaling pathways into membrane trafficking routes and its physiological relevance for immune responses is still largely unclear. In this study, using Lyst-mutant beige mice, we show that lysosomal trafficking regulator Lyst links endolysosomal organization to the selective control of toll-like receptor 3 (TLR3)– and TLR4-mediated proinflammatory responses. Consequently, Lyst-mutant mice showed increased susceptibility to bacterial infection and were largely resistant to endotoxin-induced septic shock. Mechanistic analysis revealed that Lyst specifically controls TLR3- and TLR4-induced endosomal TRIF (TIR domain–containing adapter-inducing interferon β) signaling pathways. Loss of functional Lyst leads to dysregulated phagosomal maturation, resulting in a failure to form an activation-induced Rab7+ endosomal/phagosomal compartment. This specific Rab7+ compartment was further demonstrated to serve as a major site for active TRIF signaling events, thus linking phagosomal maturation to specific TLR signaling pathways. The immunoregulatory role of Lyst on TLR signaling pathways was confirmed in human cells by CRISPR/Cas9-mediated gene inactivation. As mutations in LYST cause human Chédiak-Higashi syndrome, a severe immunodeficiency, our findings also contribute to a better understanding of human disease mechanisms.

scholarly journals Toll-Like Receptor 4 Agonistic Antibody Promotes Host Defense against Chronic Pseudomonas aeruginosa Lung Infection in Mice

2016 ◽  
Vol 84 (7) ◽  
pp. 1986-1993 ◽  
Author(s):  
Shigeki Nakamura ◽  
Naoki Iwanaga ◽  
Masafumi Seki ◽  
Kenji Fukudome ◽  
Kazuhiro Oshima ◽  
...  
Keyword(s):  
Immune Response ◽  
Pseudomonas Aeruginosa ◽  
Neutrophil Recruitment ◽  
Dependent Manner ◽  
Bacterial Clearance ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Content Type ◽  
Opsonophagocytic Killing

Chronic lower respiratory tract infection withPseudomonas aeruginosais difficult to treat due to enhanced antibiotic resistance and decreased efficacy of drug delivery to destroyed lung tissue. To determine the potential for restorative immunomodulation therapies, we evaluated the effect of Toll-like receptor 4 (TLR4) stimulation on the host immune response toPseudomonasinfection in mice. We implanted sterile plastic tubes precoated withP. aeruginosain the bronchi of mice, administered the TLR4/MD2 agonistic monoclonal antibody UT12 intraperitoneally every week, and subsequently analyzed the numbers of viable bacteria and inflammatory cells and the levels of cytokines. We also performed flow cytometry-based phagocytosis and opsonophagocytic killing assaysin vitrousing UT12-treated murine peritoneal neutrophils. UT12-treated mice showed significantly enhanced bacterial clearance, increased numbers of Ly6G+neutrophils, and increased concentrations of macrophage inflammatory protein 2 (MIP-2) in the lungs (P< 0.05). Depletion of CD4+T cells eliminated the ability of the UT12 treatment to improve bacterial clearance and promote neutrophil recruitment and MIP-2 production. Additionally, UT12-pretreated peritoneal neutrophils exhibited increased opsonophagocytic killing activity via activation of the serine protease pathway, specifically neutrophil elastase activity, in a TLR4-dependent manner. These data indicated that UT12 administration significantly augmented the innate immune response against chronic bacterial infection, in part by promoting neutrophil recruitment and bactericidal function.

scholarly journals Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Lucile Moynié ◽  
Alexandre Luscher ◽  
Dora Rolo ◽  
Daniel Pletzer ◽  
Antoni Tortajada ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Rational Design ◽  
Transport Systems ◽  
Gram Negative ◽  
Content Type ◽  
Drug Conjugates ◽  
Membrane Complex ◽  
And Function ◽  
Drug Receptors

ABSTRACT The outer membrane of Gram-negative bacteria presents an efficient barrier to the permeation of antimicrobial molecules. One strategy pursued to circumvent this obstacle is to hijack transport systems for essential nutrients, such as iron. BAL30072 and MC-1 are two monobactams conjugated to a dihydroxypyridone siderophore that are active against Pseudomonas aeruginosa and Acinetobacter baumannii. Here, we investigated the mechanism of action of these molecules in A. baumannii. We identified two novel TonB-dependent receptors, termed Ab-PiuA and Ab-PirA, that are required for the antimicrobial activity of both agents. Deletion of either piuA or pirA in A. baumannii resulted in 4- to 8-fold-decreased susceptibility, while their overexpression in the heterologous host P. aeruginosa increased susceptibility to the two siderophore-drug conjugates by 4- to 32-fold. The crystal structures of PiuA and PirA from A. baumannii and their orthologues from P. aeruginosa were determined. The structures revealed similar architectures; however, structural differences between PirA and PiuA point to potential differences between their cognate siderophore ligands. Spontaneous mutants, selected upon exposure to BAL30072, harbored frameshift mutations in either the ExbD3 or the TonB3 protein of A. baumannii, forming the cytoplasmic-membrane complex providing the energy for the siderophore translocation process. The results of this study provide insight for the rational design of novel siderophore-drug conjugates against problematic Gram-negative pathogens.

scholarly journals Nucleoside Diphosphate Kinase and Flagellin from Pseudomonas aeruginosa Induce Interleukin 1 Expression via the Akt/NF-κB Signaling Pathways

2014 ◽  
Vol 82 (8) ◽  
pp. 3252-3260 ◽  
Author(s):  
Yong-Jae Kim ◽  
Jung-Hoon Lee ◽  
Yeji Lee ◽  
Jingyue Jia ◽  
Se-Hwan Paek ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Proinflammatory Cytokines ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Nucleoside Diphosphate Kinase ◽  
Polymorphonuclear Neutrophils ◽  
Content Type ◽  
The Many

ABSTRACTInflammatory responses are a first line of host defense against a range of invading pathogens, consisting of the release of proinflammatory cytokines followed by attraction of polymorphonuclear neutrophils (PMNs) to the site of inflammation. Among the many virulence factors that contribute to the pathogenesis of infections, nucleoside diphosphate kinase (Ndk) mediates bacterially induced toxicity against eukaryotic cells. However, no study has examined how Ndk affects inflammatory responses. The present study examined the mechanisms by whichPseudomonas aeruginosaactivates inflammatory responses upon infection of cells. The results showed that bacterial Ndk, with the aid of an additional bacterial factor, flagellin, induced expression of the proinflammatory cytokines interleukin-1α (IL-1α) and IL-1β. Cytokine induction appeared to be dependent on the kinase activity of Ndk and was mediated via the NF-κB signaling pathway. Notably, Ndk activated the Akt signaling pathway, which acts upstream of NF-κB, as well as caspase-1, which is a key component of inflammasome. Thus, this study demonstrated thatP. aeruginosa, through the combined effects of Ndk and flagellin, upregulates the expression of proinflammatory cytokines via the Akt/NF-κB signaling pathways.

scholarly journals Role of Toll Interleukin-1 Receptor (IL-1R) 8, a Negative Regulator of IL-1R/Toll-Like Receptor Signaling, in Resistance to Acute Pseudomonas aeruginosa Lung Infection

2011 ◽  
Vol 80 (1) ◽  
pp. 100-109 ◽  
Author(s):  
Tania Véliz Rodriguez ◽  
Federica Moalli ◽  
Nadia Polentarutti ◽  
Moira Paroni ◽  
Eduardo Bonavita ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Interleukin 1 ◽  
Bacterial Load ◽  
Lung Infection ◽  
Negative Regulator ◽  
Current Evidence ◽  
Toll Like Receptor ◽  
Content Type ◽  
Deficient Mice

ABSTRACTToll interleukin-1 receptor (IL-1R) 8 (TIR8), also known as single Ig IL-1 receptor (IL-R)-related molecule, or SIGIRR, is a member of the IL-1R-like family, primarily expressed by epithelial cells. Current evidence suggests that TIR8 plays a nonredundant role as a negative regulatorin vivounder different inflammatory conditions that are dependent on IL-R and Toll-like receptor (TLR) activation. In the present study, we examined the role of TIR8 in innate resistance to acute lung infections caused byPseudomonas aeruginosa, a Gram-negative pathogen responsible for life-threatening infections in immunocompromised individuals and cystic fibrosis patients. We show that Tir8 deficiency in mice was associated with increased susceptibility to acuteP. aeruginosainfection, in terms of mortality and bacterial load, and to exacerbated local and systemic production of proinflammatory cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], IL-1β, and IL-6) and chemokines (CXCL1, CXCL2, and CCL2). It has been reported that host defense againstP. aeruginosaacute lung infection can be improved by blocking IL-1 since exaggerated IL-1β production may be harmful for the host in this infection. In agreement with these data, IL-1RI deficiency rescues the phenotype observed in Tir8-deficient mice: in Tir8−/−IL-1RI−/−double knockout mice we observed higher survival rates, enhanced bacterial clearance, and reduced levels of local and systemic cytokine and chemokine levels than in Tir8-deficient mice. These results suggest that TIR8 has a nonredundant effect in modulating the inflammation caused byP. aeruginosa, in particular, by negatively regulating IL-1RI signaling, which plays a major role in the pathogenesis of this infectious disease.

scholarly journals Regulation of systemic and local neutrophil responses by G-CSF during pulmonary Pseudomonas aeruginosa infection

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3235-3243 ◽  
Author(s):  
Alyssa D. Gregory ◽  
Lisa A. Hogue ◽  
Thomas W. Ferkol ◽  
Daniel C. Link
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Neutrophil Accumulation ◽  
Agarose Beads ◽  
Inflammatory Site ◽  
Inflammatory Chemokines ◽  
Pseudomonas Aeruginosa Infection ◽  
High Concentrations ◽  
And Function ◽  
Neutrophil Survival ◽  
Neutrophil Response

AbstractGranulocyte colony-stimulating factor (G-CSF) regulates the production, maturation, and function of neutrophils. Its expression is often induced during infection, resulting in high concentrations of G-CSF in inflammatory exudates and in the blood, suggesting that it may regulate both local and systemic neutrophil responses. Herein, we characterize the neutrophil response in G-CSFR−/− mice following intratracheal injection with Pseudomonas aeruginosa–laden agarose beads, modeling the pulmonary infection observed in many patients with cystic fibrosis. G-CSFR−/− mice are markedly susceptible to bronchopulmonary P aeruginosa infection, exhibiting decreased survival and bacterial clearance as well as extensive damage to lung tissue. The systemic neutrophil response was mediated primarily by enhanced neutrophil release from the bone marrow rather than increased neutrophil production and was attenuated in G-CSFR−/− mice. Despite normal to increased local production of inflammatory chemokines, neutrophil accumulation into the infected lung of G-CSFR−/− mice was markedly reduced. Moreover, the percentage of apoptotic neutrophils in the lung was elevated, suggesting that G-CSF signals may play an important role in regulating neutrophil survival at the inflammatory site. Collectively, these data provide new evidence that G-CSF signals play important but specific roles in the regulation of the systemic and local neutrophil response following infection.

scholarly journals 17β-Estradiol Dysregulates Innate Immune Responses to Pseudomonas aeruginosa Respiratory Infection and Is Modulated by Estrogen Receptor Antagonism

2017 ◽  
Vol 85 (10) ◽  
Author(s):  
Shadaan Abid ◽  
ShangKui Xie ◽  
Moumita Bose ◽  
Philip W. Shaul ◽  
Lance S. Terada ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Estrogen Receptor ◽  
Immune Responses ◽  
Sex Hormones ◽  
Inflammatory Responses ◽  
Human Subjects ◽  
Content Type ◽  
Female Mice ◽  
17Β Estradiol ◽  
The Impact

ABSTRACT Females have a more severe clinical course than males in terms of several inflammatory lung conditions. Notably, females with cystic fibrosis (CF) suffer worse outcomes, particularly in the setting of Pseudomonas aeruginosa infection. Sex hormones have been implicated in experimental and clinical studies; however, immune mechanisms responsible for this sex-based disparity are unknown and the specific sex hormone target for therapeutic manipulation has not been identified. The objective of this study was to assess mechanisms behind the impact of female sex hormones on host immune responses to P. aeruginosa. We used wild-type and CF mice, which we hormone manipulated, inoculated with P. aeruginosa, and then examined for outcomes and inflammatory responses. Neutrophils isolated from mice and human subjects were tested for responses to P. aeruginosa. We found that female mice inoculated with P. aeruginosa died earlier and showed slower bacterial clearance than males (P < 0.0001). Ovariectomized females supplemented with 17β-estradiol succumbed to P. aeruginosa challenge earlier than progesterone- or vehicle-supplemented mice (P = 0.0003). 17β-Estradiol-treated ovariectomized female mice demonstrated increased lung levels of inflammatory cytokines, and when rendered neutropenic the mortality difference was abrogated. Neutrophils treated with 17β-estradiol demonstrated an enhanced oxidative burst but decreased P. aeruginosa killing and earlier cell necrosis. The estrogen receptor (ER) antagonist ICI 182,780 improved survival in female mice infected with P. aeruginosa and restored neutrophil function. We concluded that ER antagonism rescues estrogen-mediated neutrophil dysfunction and improves survival in response to P. aeruginosa. ER-mediated processes may explain the sex-based mortality gap in CF and other inflammatory lung illnesses, and the ER blockade represents a rational therapeutic strategy.

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