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In vivo screening for essential metabolic mediators in mouse model of lung inflammation using AAV9-ME CRISPR library

ABSTRACT: Timely termination of innate immune response and resolution of inflammation is critical for preventing tissue damage and keeping homeostasis. Immunometabolism is verified to be important in innate immunity and inflammation. However, metabolic processes and related enzymes involved in inflammatory resolution remain largely unknown. To identify the key mediators in the metabolic regulation of inflammation resolution, we generated an AAV9-ME CRISPR library containing 17090 sgRNAs targeting 2682 mouse metabolic genes and performed an in vivo CRISPR screen in influenza virus (IAV) infection-induced lung inflammation model in Sftpc-Cas9 mice. We found that a very long chain fatty acid elongase, ELOVL5, could promote the resolution of lung inflammation. These results provide evidence for the metabolic gene-mediated regulation of immune inflammation and also insights for treating inflammatory diseases through manipulating metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE298405 | GEO | 2025/11/18

REPOSITORIES: GEO

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Project description:Salmonella causes inflammation in infected hosts. Inflammation is a well-characterized defensive mechanism of innate immunity. The recognition and engagement of lipopolysaccharide (LPS) endotoxins in the outer membranes of Salmonella to Toll-like receptor 4 of immune cells (macrophages and dendritic cells) trigger inflammatory responses characterized by secretion of pro-inflammatory cytokines, including TNF-beta, IL-1 and IL-6. These cytokines cause fever, anorexia, bodyweight losses, and catabolism of skeletal muscles and adipose tissues. However, molecular events underlying innate immune responses and metabolic activities during the later stage of inflammation are poorly understood. Additionally, the effects of prebiotics and antibiotics on innate immunity and nutrient metabolism are not yet reported. The objective of this study is to investigate the effects of a mannanoligosaccharide (MOS) prebiotic and virginiamycin (VIRG) sub-therapeutic antibiotic on innate immunity and glucose metabolism during late inflammation. We induced Salmonella LPS-systemic inflammation in a chicken model. Differentially regulated gene expressions were measured using 2 colour focussed oligonucleotide chicken-specific microarrays. Microarray analysis was performed on liver, intestinal and skeletal muscle tissues. We found that late inflammation was principally modulated by interleukin 3 (IL 3) and that glucose was mobilized from gluconeogenesis occurring in the intestines only. MOS and VIRG modulated innate immunity and metabolic genes differently. In contrast to VIRG, MOS terminated inflammatory responses earlier. Our results indicate IL 3 gene up-regulation in VIRG-fed chickens. To meet the higher energy requirements of VIRG chickens, genes for intestinal gluconeogenesis and liver glycolysis were respectively induced. Our study reveals the potential mechanisms by which prebiotic and antibiotic modulated innate immunity and glucose metabolism during late inflammation. 14-day old chickens were injected i.p. with saline or LPS. For each tissue and experimental conditions (saline or LPS challenge), a total of 12 microarrays (6 MOS birds + 6 VIRG birds) were used in a 2 x 2 factorial design and complete interwoven loop arrangement. We compared gene expression from prebiotic-fed birds with antibiotic-fed birds without including reference RNA. LPS challenge, antibiotic or prebiotic, innate immunity, glucose metabolism

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In vivo screening for essential metabolic mediators in mouse model of lung inflammation using AAV9-ME CRISPR library

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