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Cell-specific Interleukin-15 and Interleukin-15 receptor subunit expression and regulation in pneumococcal pneumonia

ABSTRACT: IL-15 has critical impact on the homeostasis and activation of NK, NKT, gdT and CD8+T cells, and contributes to antimicrobial defenses particularly at mucosal sites. The respiratory tract also comprises a large mucosal surface and harbors significant amounts of lymphocytes, but the expression pattern of IL-15 in the lung and its role in local immune responses are largely unknown. We therefore analyzed the differential expression of IL-15 and the IL-15 receptor (IL-15R) complex in the lungs of mice, and demonstrated substantial constitutive expression in bronchial and alveolar epithelial cells, alveolar macrophages, and vascular smooth muscle cells, implicating contribution to pulmonary immune cell homeostasis already under normal conditions. The induction of pneumococcal pneumonia but not the infection with Chlamydophila pneumoniae evoked a significant up-regulation of IL-15 on alveolar macrophages and bronchial epithelial cells, with the latter presenting de-novo expression of IL-15 on their basolateral surface and additional up-regulation of IL-15Ra . Transcriptome analysis and semiquantitative PCR indicated at least partial transcriptional regulation. Finally, the increase of IL-15 was accompanied by enhanced expression of CD69, TNFa, IFNg and Bcl-2 by IL-15-dependent lymphocyte populations suggesting functional impact of IL-15 on the pulmonary immune response in pneumococcal pneumonia. Keywords: Streptococcus pneumoniae, pneumonia, IL-15

ORGANISM(S): Mus musculus

PROVIDER: GSE3631 | GEO | 2006/03/01

SECONDARY ACCESSION(S): PRJNA93743

REPOSITORIES: GEO

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Cell-specific Interleukin-15 and Interleukin-15 receptor subunit expression and regulation in pneumococcal pneumonia

Project description:IL-15 has critical impact on the homeostasis and activation of NK, NKT, gdT and CD8+T cells, and contributes to antimicrobial defenses particularly at mucosal sites. The respiratory tract also comprises a large mucosal surface and harbors significant amounts of lymphocytes, but the expression pattern of IL-15 in the lung and its role in local immune responses are largely unknown. We therefore analyzed the differential expression of IL-15 and the IL-15 receptor (IL-15R) complex in the lungs of mice, and demonstrated substantial constitutive expression in bronchial and alveolar epithelial cells, alveolar macrophages, and vascular smooth muscle cells, implicating contribution to pulmonary immune cell homeostasis already under normal conditions. The induction of pneumococcal pneumonia but not the infection with Chlamydophila pneumoniae evoked a significant up-regulation of IL-15 on alveolar macrophages and bronchial epithelial cells, with the latter presenting de-novo expression of IL-15 on their basolateral surface and additional up-regulation of IL-15Ra . Transcriptome analysis and semiquantitative PCR indicated at least partial transcriptional regulation. Finally, the increase of IL-15 was accompanied by enhanced expression of CD69, TNFa, IFNg and Bcl-2 by IL-15-dependent lymphocyte populations suggesting functional impact of IL-15 on the pulmonary immune response in pneumococcal pneumonia. Microarray experiments were done as two-color hybridizations. RNA labeling was performed with a Fluorescent Linear Amplification Kit (Agilent Technologies). In order to compensate dye specific effects, and to ensure statistically relevant data, a color swap was performed.

2010-07-01 | E-GEOD-3631 | biostudies-arrayexpress

PCR array of inflammatory cytokines and receptors in mouse lungs with NF-kappaB RelA mutant in alveolar epithelial cells during pneumococcal pneumonia

2012-08-03 | GSE38399 | GEO

Smith2011 - Three Stage Innate Immune Response to a Pneumococcal Lung Infection

Project description:Pneumococcal pneumonia is a leading cause of death and a major source of human morbidity. The initial immune response plays a central role in determining the course and outcome of pneumococcal disease. We combine bacterial titer measurements from mice infected with Streptococcus pneumoniae with mathematical modeling to investigate the coordination of immune responses and the effects of initial inoculum on outcome. To evaluate the contributions of individual components, we systematically build a mathematical model from three subsystems that describe the succession of defensive cells in the lung: resident alveolar macrophages, neutrophils and monocyte-derived macrophages. The alveolar macrophage response, which can be modeled by a single differential equation, can by itself rapidly clear small initial numbers of pneumococci. Extending the model to include the neutrophil response required additional equations for recruitment cytokines and host cell status and damage. With these dynamics, two outcomes can be predicted: bacterial clearance or sustained bacterial growth. Finally, a model including monocyte-derived macrophage recruitment by neutrophils suggests that sustained bacterial growth is possible even in their presence. Our model quantifies the contributions of cytotoxicity and immune-mediated damage in pneumococcal pathogenesis.

2020-03-26 | BIOMD0000000924 | BioModels

PCR array of inflammatory cytokines and receptors in mouse lungs with NF-kappaB RelA mutant in alveolar epithelial cells during pneumococcal pneumonia

Project description:A murine model of RelA mutated throughout the alveolar epithelium was generated. Mice were anesthetized and intratracheally instilled with 106 CFU of Streptococcus pneumoniae serotype 3 into the left lung lobe. Mice were euthanized after 15 hours after instillation, and left lung lobes were collected to isolate RNA. We used SABioscience Mouse Inflammatory Cytokines and Receptors PCR Array to evaluate whether the expressions of lung cytokines and receptors during pneumococcal pneumonia are dependent on alveolar epithelial NF-M-NM-:B RelA or not. qPCR gene expression profiling. RNA were collected from six different mouse lungs in each genotype (wild-type and alveolar epithelial RelA mutant). Equal amount of RNA (200ng) was pooled from six different mouse lungs, and 1M-NM-<g of total RNA (1.2M-NM-<g) was used to the PCR array.

2012-08-03 | E-GEOD-38399 | biostudies-arrayexpress

Role of Mincle overexpression in pneumococcal pneumonia

Project description:Macrophage-inducible C-type lectin (Mincle) dependent sensing of pathogens trig-gers proinflammatory immune responses in professional phagocytes that contribute to protect the host against pathogen invasion. Here, we examined whether overex-pression of Mincle designed to improve early pathogen sensing by professional phagocytes would improve lung protective immunity against Streptococcus pneu-moniae in mice. Proteomic profiling of alveolar macrophages (AM) of Mincle trans-genic (tg) mice stimulated with the Mincle-specific pneumococcal ligand glucosyl-diacylglycerol (Glc-DAG) revealed increased Nlrp3 inflammasome activation and downstream IL-1 cytokine release that was not observed in Glc-DAG stimulated Mincle KO or Nlrp3 KO macrophages. Along this line, Mincle tg mice also responded with a stronger Nlrp3 expression and early proinflammatory cytokine release after challenge with S. pneumoniae, ultimately leading to fatal pneumonia in the Mincle tg mice. Importantly, Nlrp3 inhibitor treatment of Mincle tg mice significantly mitigated the observed hyperinflammatory response to pneumococcal challenge. Together, we show that overexpression of the pattern recognition receptor Mincle triggers in-creased Glc-DAG dependent Nlrp3 inflammasome activation in professional phago-cytes leading to fatal pneumococcal pneumonia in mice, which is amenable to Nlrp3 inhibitor treatment. These data show that ectopic expression of Mincle receptor con-fers increased susceptibility rather than resistance to S. pneumoniae in mice, thus highlighting the importance of an inducible Mincle receptor expression in response to microbial challenge.

2020-10-05 | PXD018752 | Pride

IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota [shotgun sequencing]

Project description:IL-22 plays a critical role in defending against mucosal infections, but how IL-22 production is regulated is incompletely understood. Here, we show that mice lacking IL-33 or its receptor ST2 (IL-1RL1) were more resistant to Streptococcus pneumoniae lung infection than wild-type animals, and that single nucleotide polymorphisms in IL33 and IL1RL1 were associated with pneumococcal pneumonia in humans. The effect of IL-33 on S. pneumoniae infection was mediated by negative regulation of IL-22 production by innate lymphoid cells (ILCs), but independent of ILC2s as well as IL-4 and IL-13 signaling. Moreover, IL-33´s influence on antibacterial defense was dependent on housing conditions of the mice, and mediated by the modulatory effect of IL-33 on the intestinal microbiota. Collectively, we reveal that IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota. Our study thus provides insight into the bidirectional crosstalk between the innate immune system and the microbiota and how it shapes susceptibility to bacterial infection.

2024-03-19 | GSE236343 | GEO

IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota [scRNA-seq]

2024-03-19 | GSE236342 | GEO

IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota [bulk RNA-seq]

Project description:IL-22 plays a critical role in defending against mucosal infections, but how IL-22 production is regulated is incompletely understood. Here, we show that mice lacking IL-33 or its receptor ST2 (IL-1RL1) were more resistant to Streptococcus pneumoniae lung infection than wild-type animals, and that single nucleotide polymorphisms in IL33 and IL1RL1 were associated with pneumococcal pneumonia in humans. The effect of IL-33 on S. pneumoniae infection was mediated by negative regulation of IL-22 production by innate lymphoid cells (ILCs), but independent of ILC2s as well as IL-4 and IL-13 signaling. Moreover, IL-33´s influence on antibacterial defense was dependent on the housing conditions of the mice, and mediated by IL-33´s modulatory effect on the intestinal microbiota. Collectively, we reveal that IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota. Our study thus provides insight into the bidirectional crosstalk between the innate immune system and the microbiota and how it shapes susceptibility to bacterial infection.

2024-03-19 | GSE236341 | GEO

Mechanistic and structural insight into the functional dichotomy between interleukin-2 and interleukin-15

Project description:Interleukin-15 (IL-15) and IL-2 possess distinct immunological functions despite both signaling through IL-2Rβ and the common cytokine receptor γ-chain, γc, We find that in the IL-15/IL-15Rα/IL-2Rβ/γc quaternary complex structure, IL-15 heterodimerizes IL-2Rβ and γc identically to the IL-2/IL-2Rα/IL-2Rβ/γc complex, despite differing receptor-binding chemistries. IL-15Rα dramatically increases the affinity of IL-15 for IL-2Rβ, and this allostery is required for IL-15 trans-signaling versus IL-2 cis-signaling. Consistent with the identical IL-2Rβ/γc dimer geometry, IL-2 and IL-15 exhibited similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induce similar signals, and the cytokine-specificity of IL-2Rα versus IL-15Rα determines cellular responsiveness. These results provide important new insights for specific development of IL-15- versus IL-2-based immunotherapeutics.

2012-11-01 | GSE40350 | GEO

Reprogrammed alveolar macrophages after pneumonia recovery

Project description:Community-acquired pneumonia is a widespread disease with significant morbidity and mortality. Alveolar macrophages are tissue-resident lung cells that play a crucial role in innate immunity against bacteria causing pneumonia. We hypothesized that alveolar macrophages display adaptive characteristics after resolution of bacterial pneumonia. We studied mice one to six months after self-limiting lung infection due to Streptococcus pneumoniae, the most common cause of bacterial pneumonia. Among the myeloid cells recovered from the lung, only alveolar macrophages showed long-term modifications of their surface marker phenotype. The remodeling of alveolar macrophages was: (i) long-lasting (still observed 6 months post infection), (ii) regionally localized (only observed in the affected lobe after lobar pneumonia), and (iii) associated with a macrophage-dependent enhanced lung protection to another pneumococcal serotype. Metabolomic and transcriptomic profiling revealed that alveolar macrophages of mice which recovered from pneumonia had new baseline activities and altered responses to infection. Thus, the enhanced lung protection after mild and self-limiting respiratory infection includes a profound remodeling of alveolar macrophages that is long-lasting, compartmentalized, and manifest across surface receptors, metabolites, and both resting and stimulated transcriptomes. We used microarrays to detail the global program of gene expression for mouse alveolar macrophages sorted from lungs that were naïve or infected more than a month previously, at rest and during an acute (4-hour) infection.

2020-04-17 | GSE133975 | GEO

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