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Exogenous remodeling of the lung macrophage microenvironment protects against infectious consequences of bone marrow ablative chemotherapy

ABSTRACT: Infection is the single greatest threat to survival during cancer chemotherapy because of depletion of bone marrow derived immune cells. In the absence of phagocytes such as neutrophil, vaccine-induced humoral and cellular anti-pathogen immunity are compromised. Using a model of vaccine-induced protection against lethal P. aeruginosa pneumonia in the setting of chemotherapy-induced neutropenia, we found a population of resident lung macrophages in the immunized lung that mediated protection in the absence of neutrophils, bone marrow derived monocytes, or antibodies. These vaccine-induced macrophages (ViMs) expanded after immunization, locally proliferated, and were closely related to alveolar macrophages (AMs) by surface phenotype and gene expression profiles. By contrast to AMs, numbers of ViMs were stable through chemotherapy, show enhanced phagocytic activity, and prolonged survival of neutropenic mice from lethal P. aeruginosa pneumonia upon intratracheal adoptive transfer. Thus, induction of ViMs by tissue macrophage remodeling may become a framework for new strategies to activate immune-mediated reserves against infection in immunocompromised hosts.

ORGANISM(S): Mus musculus

PROVIDER: GSE85336 | GEO | 2016/09/26

SECONDARY ACCESSION(S): PRJNA338187

REPOSITORIES: GEO

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Trained immunity of alveolar macrophages promotes injury resolution by enhancing KLF4-MERTK-mediated efferocytosis

Project description:Recent studies suggest that training of innate immune cells such as tissue-resident macrophages by repeated noxious stimuli can heighten host defense responses. However, it remains unclear whether trained immunity of tissue-resident macrophages also comprises enhanced injury resolution capacity to counterbalance the heightened inflammatory responses. Here, we studied lung-resident alveolar macrophages (AMs) pre-challenged with either the bacterial endotoxin or with Pseudomonas aeruginosa and observed that these trained AMs showed greater resilience to pathogen-induced cell death. Transcriptomic analysis, and functional assays showed greater capacity of trained AMs to efferocytosis of cellular- debris, and facilitate injury resolution. Single-cell high-dimensional mass-cytometry analysis and lineage tracing demonstrated that training induces an expansion of a MERTKhiMarcohiCD163+F4/80low lung-resident AMs subset with pro-resolving phenotypes. Training epigenetically reprogrammed AMs to express a higher level of the transcription factor KLF4 which in turn upregulates the efferocytosis receptor MERTK. Adoptive transfer of these trained AMs restricted inflammatory lung injury in recipient mice exposed to lethal Pseudomonas aeruginosa. Thus, our study has identified a unique subset of tissue-resident trained macrophages which prevent hyper-inflammation and restore tissue homeostasis following pathogen challenge.

2023-08-16 | GSE231217 | GEO

Trained immunity of alveolar macrophages promotes injury resolution by enhancing KLF4-MERTK-mediated efferocytosis [RNA-seq]

2023-08-16 | GSE231218 | GEO

Immunization with lytic polysaccharide monooxygenase CbpD induces protective immunity against Pseudomonas aeruginosa pneumonia

Project description:Bacterial lytic polysaccharide monooxygenases (LPMOs) are understudied in the context of infection disease. We demonstrated that Pseudomonas aeruginosa LPMO CbpD is a virulence determinant in pneumonia. Moreover, Mice immunized with CbpD generate robust antibody responses that provide protection against lethal lung infection

2023-07-26 | PXD039298 | Pride

Gene expression in mouse lung epithelial cells treated with synthetic TLR ligands to induce resistance

Project description:Infectious pneumonias exact an unacceptable mortality burden worldwide. Efforts to protect populations from pneumonia have historically focused on antibiotic development and vaccine-enhanced adaptive immunity. However, we have recently reported that the lungs’ innate defenses can be therapeutically induced by inhalation of a bacterial lysate that protects mice against otherwise lethal pneumonia. Here, we tested in mice the hypothesis that Toll-like receptors (TLRs) are required for this antimicrobial phenomenon, and found that resistance could not be induced in the absence of the TLR signaling adaptor protein MyD88. We then attempted to recapitulate the protection afforded by the bacterial lysate by stimulating the lung epithelium with aerosolized synthetic TLR ligands. While most single or combination treatments yielded no protection, simultaneous treatment with ligands for TLR2/6 and TLR9 conferred robust, synergistic protection against virulent Gram-positive and Gram-negative pathogens. Protection was associated with rapid pathogen killing in the lungs, and pathogen killing could be induced from lung epithelial cells in isolation. Taken together, these data demonstrate the requirement for TLRs in inducible resistance against pneumonia, reveal a remarkable, unanticipated synergistic interaction of TLR2/6 and TLR9, reinforce the emerging evidence supporting the antimicrobial capacity of the lung epithelium, and may provide the basis for a novel clinical therapeutic that can protect patients against pneumonia during periods of peak vulnerability. MLE-15 cells were treated with 20 ul volumes of PBS (sham treatment), ODN2395 (0.4 ug), Pam2CSK4 (0.2 ug) or ODN2395+Pam2CSK4. At least 5 unique samples per group. Treated for 2 hours. Hybridized to Illumina Sentrix MouseRef-8 v2 Beadhips.

2011-01-27 | E-GEOD-26864 | biostudies-arrayexpress

Epigenetic profiles of mouse splenic macrophages responding to a Protein-Free Vaccine that Induces Trained Immunity and Protects against Nosocomial Pathogens

Project description:Traditional vaccines are difficult to deploy against the diverse antibiotic-resistant, nosocomial pathogens that cause Hospital Acquired Infections (HAIs). We developed a unique, protein-free vaccine to present antibiotic-resistant HAIs. This vaccine protected mice from invasive infections caused by methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, multidrug resistant Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Rhizopus delemar, and Candida albicans. Protection persisted even in neutropenic mice infected with A. baumannii or R. delemar. Protection was already apparent after 24 hours and lasted for up to 21 days after a single dose, with a second dose restoring efficacy. Protection persisted without lymphocytes but was abrogated with macrophages depletion. This vaccine induced trained immunity by altering the macrophage epigenetic landscape and the inflammatory response to infection.

2023-08-24 | GSE216061 | GEO

Gene expression in mouse lung homogenates treated with synthetic TLR ligands to induce resistance

2011-05-01 | GSE28994 | GEO

Gene expression in mouse lung epithelial cells treated with synthetic TLR ligands to induce resistance

2011-01-27 | GSE26864 | GEO

Gene expression in mouse lung homogenates treated with synthetic TLR ligands to induce resistance

Project description:Infectious pneumonias exact an unacceptable mortality burden worldwide. Efforts to protect populations from pneumonia have historically focused on antibiotic development and vaccine-enhanced adaptive immunity. However, we have recently reported that the lungs’ innate defenses can be therapeutically induced by inhalation of a combination of synthetic TLR ligands that synergize to protect mice against otherwise lethal pneumonia. Simultaneous treatment with ligands for TLR2/6 and TLR9 conferred robust, synergistic protection against virulent Gram-positive and Gram-negative pathogens, as well as viruses. Protection is associated with rapid pathogen killing in the lungs, and pathogen killing can be induced from lung epithelial cells in isolation. Here we explore the mechanisms underlying this dramatic phenomenon by performing microarray gene expression analysis of mouse lungs treated by aerosol with PBS (sham treatment), Pam2CSK4 (TLR 2/6 ligand), ODN2395 (TLR9 ligand), or both TLR ligands. C57BL/6J mice were placed, unrestrained, in a aerosolization chamber and inhalationally exposed to 20 minute treatment with an 8 ml volume of PBS (sham), Pam2CSK4 10 ug/ml, ODN 2395 20 ug/ml, or the combination. 4 h after treatment, the mice were deeply anesthetized, their lungs were harvested, homogenized, and total RNA was extracted. Amplified cRNA was hybridized to Illumina Sentrix MouseRef-8 v2 Beadhips, labeled with Cy3, and scanned on an Illumina iScan. At least 8 unique samples were obtained per condition.

2011-05-01 | E-GEOD-28994 | biostudies-arrayexpress

Lectin-like oxidized low-density receptor-1 attenuates pneumonia-induced lung injury

Project description:Identifying host factors that contribute to pneumonia incidence and severity are of utmost importance to guiding the development of more effective therapies. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor known to promote vascular injury and inflammation, but it is unknown whether and how LOX-1 functions in the lung. Here, we provide evidence of substantial accumulation of LOX-1 in the lungs of ARDS patients and in mice with pneumonia. Unlike previously described injurious contributions of LOX-1, we found that LOX-1 is uniquely protective in the pulmonary airspaces, limiting proteinaceous edema and inflammation. We also identified alveolar macrophages and recruited neutrophils as two prominent sites of LOX-1 expression in the lungs, whereby macrophages are capable of further induction during pneumonia and neutrophils exhibit a rapid, but heterogenous elevation of LOX-1 in the infected lung. Blockade of LOX-1 led to dysregulated immune signaling in alveolar macrophages, marked by alterations in activation markers and a concomitant elevation of inflammatory gene networks. However, bone marrow chimeras also suggested a prominent role for neutrophils in LOX-1-mediated lung protection, further supported by LOX-1+ neutrophils exhibiting transcriptional changes consistent with reparative processes. Taken together, this work establishes LOX-1 as a tissue-protective factor in the lungs during pneumonia, possibly mediated by its influence on immune signaling in alveolar macrophages (AMs) and LOX-1+ airspace neutrophils.

2022-12-21 | GSE208233 | GEO

Multidimensional Assessment of the Host Response in Mechanically Ventilated Patients with Suspected Pneumonia

Project description:Rationale: Patients in the intensive care unit (ICU) are frequently exposed to unnecessary antibiotics. Markers of the host response to infection may aid pneumonia diagnosis and avoid antibiotic-induced complications. Objective: To assess the host response to suspected bacterial pneumonia through assessment of alveolar neutrophilia and transcriptomic profiling of alveolar macrophages. Methods: We determined the test characteristics of BAL neutrophilia for the diagnosis of bacterial pneumonia in 3 cohorts of mechanically ventilated patients. In one cohort, we also isolated alveolar macrophages from BAL fluid and used the transcriptome to identify signatures of bacterial pneumonia. Finally, we developed a humanized mouse model of Pseudomonas aeruginosa pneumonia to determine if pathogen-specific signatures can be identified in human alveolar macrophages. Measurements and Main Results: BAL neutrophilia was highly sensitive for bacterial pneumonia in both the retrospective (N = 851) and validation cohorts (N = 76 and N = 79) with a negative predictive value of over 90% when BAL neutrophil percentage was less than 50%. A transcriptional signature of bacterial pneumonia was present in both resident and recruited macrophages. Gene signatures from both cell types identified patients with bacterial pneumonia with test characteristics similar to BAL neutrophilia. Conclusions: A BAL neutrophil percentage of less than 50% is highly sensitive for bacterial pneumonia. Informative transcriptomic signatures can be generated from BAL fluid obtained during routine clinical care in the ICU. The identification of novel host response biomarkers is a promising approach to aid the diagnosis and treatment of pneumonia.

2018-11-06 | GSE121871 | GEO

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