BPIFA1 Regulates Interferon-Mediated Lung Neutrophil Recruitment During Acute Inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE104214 | GEO | 2017/09/26
SECONDARY ACCESSION(S): PRJNA412049
REPOSITORIES: GEO
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2023-09-06 | GSE218660 | GEO
Project description:Background: Environmental lipopolysaccharide (LPS) and microbial component-enriched organic dusts cause significant lung diseases. These environmental exposures induce the recruitment and activation of distinct lung monocyte/macrophage subpopulations involved in disease pathogenesis. Given monocyte/macrophage activation is tightly linked to metabolism, the objective of these studies was to determine the role of the immunometabolic regulator, aconitate decarboxylase 1 (ACOD1), in environmental exposure-induced lung inflammation. Methods: Wild-type (WT) mice were intratracheally instilled (I.T.) with 10 ug LPS or saline. Whole lungs were profiled using bulk RNA sequencing or sorted to isolate monocyte/macrophage subpopulations. Sorted subpopulations were then characterized transcriptomically using a NanoString innate immunity multiplex array 48 hours post-exposure. Next, WT and Acod1-/- mice were instilled with LPS, 25% organic dust extract (ODE), or saline with serum, bronchoalveolar lavage fluid (BALF), and lung tissues collected. BALF metabolites of the tricarboxylic acid (TCA) cycle were quantified by mass-spectrometry. Cytokines/chemokines and tissue remodeling mediators were quantitated by ELISA. Lung immune cells were characterized by flow cytometry. Whole body plethysmography was performed 3 hours post-LPS with WT and Acod1-/- mice. Results: By bulk sequencing, Acod1 was one of the most significantly upregulated genes following LPS (vs. saline) exposure of murine whole lungs. Transcriptomic profiling of sorted lung monocyte/macrophage subpopulations corroborated Acod1 significance. Acod1-/- mice treated with LPS (vs. WT) demonstrated decreased BALF levels of itaconate, TCA cycle reprogramming, decreased BALF neutrophils, increased lung CD4+ T cells, decreased BALF and lung levels of TNF-a, and decreased BALF CXCL1. In comparison, Acod1-/- mice treated with ODE (vs. WT) demonstrated decreased serum pentraxin-2, BALF levels of itaconate, lung total cell, neutrophil, monocyte, and B cell infiltrates with decreased BALF levels of TNF-a, IL-6, and decreased lung CXCL1. Mediators of tissue remodeling (TIMP1, MMP8, MMP9) were also decreased in the LPS-exposed Acod1-/- mice, with MMP-9 also decreased in the ODE-exposed Acod1-/- mice. Lung function assessments demonstrated a blunted response to LPS-induced airway hyper-responsiveness in Acod1-/- mice. Conclusion: Acod1 is robustly upregulated in the lungs following LPS-exposure and encodes a key immunometabolic regulator. ACOD1 mediates the pro-inflammatory response to acute inhaled, environmental LPS and organic dust exposure-induced lung inflammation.
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Project description:Influenza A Virus (IAV) triggers an exuberant host response that promotes acute lung injury. However, the determinants of the pathological host response to IAV remain incompletely understood. In the current study, we identified interferon (IFN)-γ-regulated subset of monocytes, CCR2+ monocytes, as a driver of lung damage during IAV pathogenesis. IFN-γ regulated the recruitment and inflammatory phenotype of CCR2+ monocytes, and CCR2 (CCR2-/-) and IFN-γ (IFN-γ-/-) deficient mice exhibited reduced lung inflammation, pathology, and increased resistance against bacterial co-infection by Streptococcus pneumoniae (Spn). Adoptive transfer of WT (IFN-γR1+), but not IFN-γR1 deficient (IFN-γR1-) CCR2+ monocytes, restored the wild-type (WT)-like pathological phenotype of lung damage in IAV-infected CCR2-/- mice. The CD8+ T cells were the most significant source of IFN-γ in IAV-infected lungs. Collectively, our data highlight that IFN-γ regulates CCR2+ monocyte-mediated lung pathology during IAV pathogenesis.
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Project description:Neutrophils play important roles in inflammatory airway diseases. Here, we assessed whether apolipoprotein A-I (apoA-I) modifies neutrophil heterogeneity as part of the mechanism by which it attenuates acute airway inflammation. Neutrophilic airway inflammation was induced by daily intranasal administration of LPS plus house dust mite (LPS+HDM) to Apoa1-/- and Apoa1+/+ mice for 3 days. Single cell RNA sequencing was performed on cells recovered in bronchoalveolar lavage fluid (BALF) on day 4. Unsupervised profiling identified 10 clusters of neutrophils in BALF from Apoa1-/- and Apoa1+/+ mice. LPS+HDM-challenged Apoa1-/- mice had an increased proportion of the Neu4 neutrophil cluster that expressed S100a8, S100a9, and Mmp8, and had high maturation, aggregation, and TLR4 binding scores. There was also an increase in the Neu6 cluster of immature neutrophils, whereas neutrophil clusters expressing interferon-stimulated genes were decreased. An unsupervised trajectory analysis showed that Neu4 represented a distinct lineage in Apoa1-/- mice. LPS+HDM-challenged Apoa1-/- mice also had an increased proportion of recruited airspace macrophages, which was associated with a reciprocal reduction in resident airspace macrophages. Increased expression of a common set of pro-inflammatory genes, S100a8, S100a9, and Lcn2, was present in all neutrophils and airspace macrophages from LPS+HDM-challenged Apoa1-/- mice. Apoa1-/- mice have increases in specific neutrophil and macrophage clusters in the lung during acute inflammation mediated by LPS+HDM, as well as enhanced expression of a common set of pro-inflammatory genes. This suggests that modifications in neutrophil and macrophage heterogeneity contribute to the mechanism by which apoA-I attenuates acute airway inflammation.
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Project description:Purpose: We characterize the changes global expression profile in peripheral macrophages induced by LPS, IFN-b, and IFN-B+LPS treatment, using bulk RNA-sequencing. Methods: mRNA profiles of bulk macrophages obtained from WT mice following treatment with either saline, IFN-b, LPS, or IFN-b+LPS. Each treatment was performed in triplicate, and RNA-sequencing was performed on the Illumina 2500. Reads passing quality metric were aligned to the mm10 genome using annotations produced by ENSEMBL, and were analyzed at the transcript level using one-way ANOVA and fold change requirements. Results: We mapped approximately 20 million reads per sample to the mm10 genome, yielding 11385 reasonably-expressed transcripts. We identified 4372 transcripts with a p-value<0.05 and fold change>2 when compared between LPS v NS, IFNb v NS, and LPS+IFNb v NS. Of these, we identified 142 genes where priming by IFNb+LPS augmented the changes in expression induced by LPS or IFNb independently. This gene set indicated that IFNb exacerbates LPS_driven proinflammatory cytokin production. Conclusion: Here we show that IFNb priming sensitizes to TLD-driven inflammation through LPS stimulation.
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Project description:The critical role of type I IFN (IFN I ) in viral disease is thoroughly documented while their function in bacterial infection remains ambiguous. General interest in biological functions of IFN I in Mycobacterium tuberculosis (Mtb) infection was raised by the identification of a distinct IFN I gene expression signature in tuberculosis (TB) patients. Here we demonstrate that TB-susceptible mice lacking the receptor for IFN I (IFNAR1) were protected from death upon aerogenic infection with Mtb. Increased survival was accompanied by reduced bacterial burden and ameliorated lung pathology as well as diminished production of proinflammatory IL-1?, among other cytokines. IFNAR1 signaling did not affect T cell responses, but markedly altered migration of inflammatory monocytes and neutrophils to the lung during pulmonary TB. This process was orchestrated by presence of IFNAR1 in both immune and tissue-resident radioresistant cells. IFNAR1-driven TB susceptibility was initiated by CXCL5/CXCL1-driven accumulation of neutrophils into alveoli and subsequently a distinct compartmentalization of Mtb in lung phagocytes. We conclude that IFN I alters early innate events at the site of Mtb invasion leading to unleashed inflammation. Hence, our data furnish a mechanistic explanation for the detrimental role of IFN I in pulmonary TB. dual-color color-swap
2013-12-31 | E-GEOD-44848 | biostudies-arrayexpress