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• W3115458882 abstract "Macrophages are versatile cells, with a repertoire of functions that regulate pro-inflammatory and anti-inflammatory responses, tissue repair, remodelling and homeostasis. These functions not only rely on the type of immunological challenge but are also highly dependent on the tissue-specific microenvironment. Alveolar macrophages (AMs) play an important role in the regulation of inflammation in the lung. In quiescent state, AMs display tolerant and anti-inflammatory properties, which in the context of their continuous exposure to the outside world and innocuous antigens are important for avoiding unwanted inflammation in the lung. This unique microenvironment and function of AMs distinguish them from other macrophage populations and results in a lack of generalizability between AMs and macrophages from other body sites. Cellular metabolism plays an important role in immune cell function.1 Cells with different immunological functions use distinct metabolic pathways to generate the required amount of energy and biosynthetic precursors. Generally, pro-inflammatory responses are associated with a shift towards glycolysis (the breakdown of glucose to pyruvate), while an anti-inflammatory profile is linked with energy generation through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS).1 These metabolic alterations occur in many macrophage subtypes including macrophage cell lines, bone marrow–derived macrophages and peritoneal macrophages.1 However, AMs reside in an environment characterized by remarkably low glucose concentrations,2 making glycolysis-linked immune activation less likely. Indeed, two recent mouse studies showed that AMs rely mostly on OXPHOS under steady-state conditions.3, 4 Furthermore, mouse AMs did not enhance glycolysis in response to lipopolysaccharide (LPS) and neither glycolysis inhibition nor glycolysis activation affected LPS-induced cytokine production in these cells.3 Instead, activated mouse AMs demonstrated increased uptake of fatty acids and upregulation of the fatty acid metabolism pathway.4 Thus far, no such studies have been performed using human AMs and therefore the extrapolation to characteristics of metabolic rewiring of AMs in the human lung remains obscure. We here leveraged genome-wide transcriptional data from AMs harvested from humans challenged with LPS in a lung subsegment by bronchoscope to obtain insight into energy metabolism adaptations in AMs stimulated with a relevant microbial component/pollutant in their natural tissue environment. The methods used have been described previously.5, 6 Briefly, seven nonsmoking healthy men (age: 21.3 ± 0.6 years, mean ± standard error of the mean) received 10 mL of sterile saline instilled into a lung subsegment followed by instillation of LPS (4 ng/kg body weight in 10 mL saline) from Escherichia coli (US Pharmacopeial Convention, Lot G, Bureau of Biologics, US Food and Drug Administration) into the contralateral lung, by using a flexible video bronchoscope. A bilateral bronchoalveolar lavage was performed 6 hours post-challenge, and AMs were isolated using CD71 microbeads (Miltenyi Biotec). RNA expression was analysed using GeneChip® Human Genome U133 Plus 2.0 arrays (Affymetrix). Gene expression data are available at the Gene Expression Omnibus public repository of NCBI under the accession number GSE40885. The study was approved by the institutional ethics and research committees of the Academic Medical Center, University of Amsterdam. Written informed consent was obtained from all subjects before study enrolment. Bronchial instillation of LPS resulted in profound changes in the transcriptome when compared with AMs harvested from the contralateral lung from the same individuals.6 LPS induced a strong enhancement of pro-inflammatory signalling pathways involved in innate immunity,6 including the prototypic cytokines genes IL-6, TNF, IL-1B and IL-10 (Figure 1A), indicating that LPS was capable of activating AMs in their natural environment in vivo. We here set out to analyse which metabolic pathways could be involved in this pro-inflammatory response. The main metabolic pathways important for macrophage function are glycolysis, the pentose phosphate pathway, the TCA cycle, fatty acid metabolism and OXPHOS.1 Surprisingly, using the Reactome database (reactome.org) as annotation source, we found that almost all of these pathways were negatively enriched after LPS challenge (Figure 1B), including the fatty acid oxidation pathway, which was upregulated in murine AMs upon LPS activation.4 Only fatty acid biosynthesis was positively enriched after LPS instillation, although not significant. This made us wonder which pathways human AMs use to obtain energy and biosynthetic intermediates to support their effector functions. We found that the tryptophan and polyamine metabolism pathways were upregulated upon LPS challenge (Figure 1C). Concordant with our results, a recent publication reported increased tryptophan metabolism in human AMs stimulated with LPS in vitro, as demonstrated by reduced tryptophan and increased kynurenine and quinolinic acid levels, measured by targeted metabolomics analysis.7 Tryptophan metabolism is regarded as a major mechanism of immune tolerance, but is also associated with proliferation of T cells, as well as preventing the growth of bacterial and parasitic pathogens by depleting this substrate. At present, the role of tryptophan metabolism in AMs is unclear. Polyamines are naturally occurring, ubiquitously distributed amino acids synthesized from l-ornithine by ornithine decarboxylase, which play a role in metabolic and genetic regulation and cell proliferation. Rising intracellular polyamine levels then induce the transcription of OAZ genes encoding for the protein antizyme, a negative regulator of ornithine decarboxylase.8 The high induction of OAZ2 and AZIN2, an antizyme inhibitor, in LPS-challenged AMs therefore indicates increased polyamine levels in these cells. Polyamine metabolism is associated with an anti-inflammatory response in macrophages: it competes for arginine availability, thereby inhibiting nitric oxide production and subsequently reducing inflammasome activation and pro-inflammatory cytokine production upon LPS stimulation.9 One polyamine, spermidine, has been shown to induce autophagy,9 which in itself has important roles in macrophage function including xenophagy, LC3-associated phagocytosis, production and delivery of antimicrobial peptides, and control of inflammasome activation.10 Furthermore, polyamines can affect chromatin conformation in various manners.11 Increased polyamine levels induce histone acetyltransferase enzymes resulting in enhanced gene expression. Moreover, competition for S-adenosylmethionine as a methionine backbone or methyl donor in both polyamine metabolism and DNA and histone methylation may lead to DNA hypomethylation resulting in gene induction. In contrast, it has also been shown that enhanced polyamine levels promote chromatin condensation and gene repression.11 These observations would support the polyamine-mediated suppression of inflammatory cytokine production upon LPS stimulation in macrophages. We here show that the classic metabolic pathways important for macrophage functions1 are not upregulated in human AMs upon LPS challenge in vivo. Instead, we found tryptophan and polyamine metabolism pathways to be upregulated. The specific inflammatory properties attributed to tryptophan and polyamine metabolism fit with the requirements of the unique microenvironment of AMs: reducing inflammation-induced damage while increasing mechanism involved in pathogen clearing such as xenophagy, the production of antimicrobial peptides and inhibiting growth of pathogens. These results set the stage for additional research to define how tryptophan and polyamine metabolism is used by human AMs to shape, regulate and support their immunological functions. The authors declare that they have no competing interests. Gene expression data are available at the Gene Expression Omnibus public repository of NCBI under the accession number GSE40885." @default.
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• W3115458882 date "2021-01-05" @default.
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• W3115458882 title "Metabolic adaptations of human alveolar macrophages upon activation by lipopolysaccharide in vivo" @default.
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• W3115458882 doi "https://doi.org/10.1111/sji.13011" @default.
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