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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE208233 | GEO | 2022/12/21

REPOSITORIES: GEO

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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

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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

SAGE analysis of alveolar macrophages from metastatic lung and untreated lung

Project description:Macrophages in lungs can be classified into two subpopulations, alveolar macrophages (AMs) and interstitial macrophages (IMs), which reside in the alveolar and interstitial spaces, respectively. Accumulating evidence indicates the involvement of IMs in lung metastasis but the roles of AMs in lung metastasis still remain elusive. An intravenous injection of a mouse hepatocellular carcinoma (HCC) cell line, BNL, caused lung metastasis foci with infiltration of AMs and IMs. Comprehensive determination of arachidonic acid (AA) metabolite levels revealed increases in leukotrienes (LTs) and prostaglandins in lungs in this metastasis model. A 5-lipoxygenase (LOX) inhibitor but not a cyclooxygenase inhibitor reduced the numbers of metastatic foci, particularly those with larger sizes. A major 5-LOX metabolite, LTB4, augmented in vitro cell proliferation of human HCC cell lines as well as BNL cells. Moreover, in this lung metastasis course, AMs exhibited higher expression levels of the 5-LOX and LTB4 than IMs. Consistently, 5-LOX-expressing AMs increased in the lungs of human HCC patients with lung metastasis, compared with those without lung metastasis. Furthermore, intratracheal clodronate liposome injection selectively depleted AMs but not IMs, together with reduced LTB4 content and metastatic foci numbers in this lung metastasis process. Finally, IMs in mouse metastatic foci produced CCL2, thereby recruiting blood-borne, CCR2-expressing AMs into lungs. Thus, AMs can be recruited under the guidance of IM-derived CCL2 into metastatic lungs and can eventually contribute to the progression of lung metastasis by providing a potent AA-derived tumor growth promoting mediator, LTB4.

2018-02-16 | GSE106987 | GEO

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2013-07-12 | E-GEOD-48787 | biostudies-arrayexpress

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2020-04-17 | PXD014967 | Pride

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2016-09-09 | GSE83612 | GEO

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2023-02-14 | GSE225316 | GEO

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Nogo-B protects mice against lipopolysaccharide-induced acute lung injury

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