Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Circadian transcriptional profiling of peritoneal macrophages

ABSTRACT: In the immune system various parameters and immune functions are controlled by the circadian system. To investigate molecular mechanisms that link the circadian clock and the immune system we analyzed the transcriptom of peritoneal macrophages from mice collected in a time course for two consecutive days. We found that more than 8% of expressed genes are under circadian control including many important regulators in pathogen recognition, signal transduction and cytokine secretion. Peritoneal macrophages from mice kept in constant conditions were isolated in 4 h intervalls over a period of 48 h. RNA of CD11b sorted cells was extracted, pooled from 3 mice per time point and used for microarray analysis.

ORGANISM(S): Mus musculus

SUBMITTER: Bert Maier

PROVIDER: E-GEOD-25585 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A circadian clock in macrophages controls inflammatory immune responses.

Keller Maren M Mazuch Jeannine J Abraham Ute U Eom Gina D GD Herzog Erik D ED Volk Hans-Dieter HD Kramer Achim A Maier Bert B

Proceedings of the National Academy of Sciences of the United States of America 20091201 50

Time of day-dependent variations of immune system parameters are ubiquitous phenomena in immunology. The circadian clock has been attributed with coordinating these variations on multiple levels; however, their molecular basis is little understood. Here, we systematically investigated the link between the circadian clock and rhythmic immune functions. We show that spleen, lymph nodes, and peritoneal macrophages of mice contain intrinsic circadian clockworks that operate autonomously even ex vivo ...[more]

PMID: 19955445

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Project description:Background: The disruption of the circadian clock is associated with inflammatory and immunological disorders. BMAL2, a critical circadian protein, forms a dimer with CLOCK, activating transcription. Extracellular cold-inducible RNA-binding protein (eCIRP), released during sepsis, can induce macrophage endotoxin tolerance. We hypothesized that eCIRP modulates BMAL2 expression and promotes macrophage endotoxin tolerance through triggering receptor expressed on myeloid cells-1 (TREM-1). Methods: C57BL/6 wild-type (WT) male mice were subjected to sepsis by cecal ligation and puncture (CLP). Serum was collected 20 hours post-CLP to assess eCIRP levels. Peritoneal macrophages (PerM) and immortalized bone marrow-derived macrophages (iBMDMs) were seeded into plates and treated with recombinant mouse (rm) CIRP (eCIRP) at various doses. Induction of BMAL2 activation in iBMDM was performed by transfection of BMAL2 CRISPR activation plasmid. Circadian gene expression profiles in eCIRP-treated macrophages were determined by PCR array and confirmed by qPCR. Cytokine levels in the culture supernatants were assessed by ELISA. The interaction of BMAL2 in the PD-L1 promoter was determined by computational modeling and confirmed by the BIAcore assay. Results: PCR array screening of circadian clock genes in peritoneal macrophages treated with eCIRP revealed the elevated expression of BMAL2, CRY1, and PER2. eCIRP serum levels were increased in septic mice. In eCIRP-treated macrophages, TREM-1 deficiency prevented the upregulation of these circadian genes. Macrophages pre-treated with eCIRP exhibited reduced TNFá and IL-6 release upon LPS challenge, indicating macrophage endotoxin tolerance. In addition, eCIRP increased the expression of PD-L1, IL-10, and STAT3, markers of immune tolerance. Interestingly, TREM-1 deficiency reversed eCIRP-induced macrophage endotoxin tolerance. In macrophages, inducible BMAL2 expression correlated with increased PD-L1 expression. In septic human patients, blood monocytes exhibited increased expression of BMAL2 and PD-L1 in comparison to healthy subjects. Computational modeling and BIAcore assay identified a putative binding region of BMAL2 in the PD-L1 promoter, suggesting BMAL2 positively regulates PD-L1 expression in macrophages. Conclusion: eCIRP upregulates BMAL2 expression via TREM-1, leading to macrophage endotoxin tolerance in sepsis. Targeting eCIRP to maintain circadian rhythm may correct endotoxin tolerance and enhance host resistance to bacterial infection.

Dataset Information

Circadian transcriptional profiling of peritoneal macrophages

Publications

A circadian clock in macrophages controls inflammatory immune responses.

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