ABSTRACT
Organisms adapt to day-night cycles through highly specialized circadian machinery, whose molecular components anticipate and drive changes in organism behavior and metabolism. Although many effectors of the immune system are known to follow daily oscillations, the role of the circadian clock in the immune response to acute infections is not understood. Here we show that the circadian clock modulates the inflammatory response during acute infection with the pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium). Mice infected with S. Typhimurium were colonized to higher levels and developed a higher proinflammatory response during the early rest period for mice, compared with other times of the day. We also demonstrate that a functional clock is required for optimal S. Typhimurium colonization and maximal induction of several proinflammatory genes. These findings point to a clock-regulated mechanism of activation of the immune response against an enteric pathogen and may suggest potential therapeutic strategies for chronopharmacologic interventions.
Subject(s)
Circadian Clocks/immunology , Cytokines/immunology , Salmonella Infections, Animal/immunology , Salmonella typhimurium/immunology , Animals , CLOCK Proteins/deficiency , CLOCK Proteins/genetics , CLOCK Proteins/immunology , Cecum/immunology , Cecum/metabolism , Cecum/microbiology , Cells, Cultured , Circadian Clocks/genetics , Cluster Analysis , Cytokines/genetics , Cytokines/metabolism , Gene Expression Profiling , Gene Regulatory Networks/genetics , Gene Regulatory Networks/immunology , Host-Pathogen Interactions/immunology , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Lipopolysaccharides/immunology , Macrophages/immunology , Macrophages/metabolism , Macrophages/microbiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Oligonucleotide Array Sequence Analysis , Reverse Transcriptase Polymerase Chain Reaction , Salmonella Infections, Animal/genetics , Salmonella Infections, Animal/microbiology , Salmonella typhimurium/physiology , Time FactorsABSTRACT
We show that mice with a targeted deficiency in the gene encoding the lipogenic transcription factor SREBP-1a are resistant to endotoxic shock and systemic inflammatory response syndrome induced by cecal ligation and puncture (CLP). When macrophages from the mutant mice were challenged with bacterial lipopolysaccharide, they failed to activate lipogenesis as well as two hallmark inflammasome functions, activation of caspase-1 and secretion of IL-1ß. We show that SREBP-1a activates not only genes required for lipogenesis in macrophages but also the gene encoding Nlrp1a, which is a core inflammasome component. Thus, SREBP-1a links lipid metabolism to the innate immune response, which supports our hypothesis that SREBPs evolved to regulate cellular reactions to external challenges that range from nutrient limitation and hypoxia to toxins and pathogens.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Apoptosis Regulatory Proteins/metabolism , Immunity, Innate , Lipid Metabolism , Macrophages/immunology , Salmonella Infections/immunology , Sterol Regulatory Element Binding Protein 1/physiology , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/genetics , Animals , Apoptosis Regulatory Proteins/antagonists & inhibitors , Apoptosis Regulatory Proteins/genetics , Blotting, Western , Bone Marrow , Caspase 1/metabolism , Cytokines/metabolism , Enzyme Activation/drug effects , Enzyme-Linked Immunosorbent Assay , Inflammasomes , Interleukin-1beta/metabolism , Lipopolysaccharides/pharmacology , Macrophages/cytology , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Reverse Transcriptase Polymerase Chain Reaction , Salmonella Infections/metabolism , Salmonella Infections/pathology , Salmonella typhimurium/immunologyABSTRACT
Local immune responses serve to contain infections by pathogens to the gut while preventing pathogen dissemination to systemic sites. Several subsets of T cells in the gut (T-helper 17 cells, gammadelta T cells, natural killer (NK), and NK-T cells) contribute to the mucosal response to pathogens by secreting a subset of cytokines including interleukin (IL)-17A, IL-17F, IL-22, and IL-26. These cytokines induce the secretion of chemokines and antimicrobial proteins, thereby orchestrating the mucosal barrier against gastrointestinal pathogens. While the mucosal barrier prevents bacterial dissemination from the gut, it also promotes colonization by pathogens that are resistant to some of the inducible antimicrobial responses. In this review, we describe the contribution of Th17 cytokines to the gut mucosal barrier during bacterial infections.
