Copper Metabolism Domain-Containing 1 Represses Genes That Promote Inflammation and Protects Mice From Colitis and Colitis-Associated Cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE53368 | GEO | 2014/05/19
SECONDARY ACCESSION(S): PRJNA231849
REPOSITORIES: GEO
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Project description:Copper is both essential and toxic to living beings, which therefore tightly control its intracellular concentration. At the host-pathogen interface, copper is used by phagocytic cells to kill invading microorganisms. We investigated copper homeostasis in the whooping cough agent Bordetella pertussis, which lives in the human respiratory mucosa and has no environmental reservoir. B. pertussis has considerably streamlined copper homeostasis mechanisms relative to other Gram-negative bacteria. Its single remaining defense line against copper intoxication consists in a metallochaperone diverted for copper passivation and two enzymes involved in peroxide detoxification, which together fight two stresses encountered in phagolysosomes. The three proteins are encoded by an original, composite operon assembled in an environmental ancestor and which is under sensitive control by copper. Interestingly, this system appears to play a role in persistent infection in the nasal cavity of B. pertussis-infected mice. Combining responses to co-occurring stresses in a tailored operon reveals a new strategy adopted by a host-restricted pathogen to optimize survival at minimal energy expenditure.
2020-10-27 | GSE145049 | GEO
Project description:Background & aimsActivation of the transcription factor nuclear factor-κB (NF-κB) has been associated with the development of inflammatory bowel disease (IBD). Copper metabolism MURR1 domain containing 1 (COMMD1), a regulator of various transport pathways, has been shown to limit NF-κB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in human beings.MethodsWe created mice with a specific disruption of Commd1 in myeloid cells (Mye-knockout [K/O] mice); we analyzed immune cell populations and functions and expression of genes regulated by NF-κB. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate, and colitis-associated cancer was induced by administration of dextran sodium sulfate and azoxymethane. We measured levels of COMMD1 messenger RNA in colon biopsy specimens from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis.ResultsIn comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed a reduced expression of COMMD1 in colon biopsy specimens and circulating leukocytes from patients with IBD. We associated single-nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis.ConclusionsExpression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.
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Project description:Inflammation is a hallmark of multiple disease processes, including inflammatory bowel disease (IBD). The transcription factor NF-kappaB plays a critical role in this response through its effects on pro-inflammatory gene expression. Consequently, homeostatic mechanisms that control NF-kappaB activity have been found to play important roles in controlling inflammatory responses in physiologic and pathologic states. Copper Metabolism Murr1 Domain containing 1 (COMMD1), a regulator of copper excretion and other transport pathways, has been shown to play a role in limiting NF-kappaB activation. However, it remains unclear if this factor plays a necessary role in the control of inflammation or in the pathogenesis of inflammatory disorders in vivo. Using a myeloid-cell specific model of Commd1 deficiency in mice we evaluated the contribution of this factor to inflammatory responses. We found that this gene plays an important role as a negative regulator of the LPS transcriptional response, and deficiency in this factor led to sensitization to in vivo models of sepsis. In addition, we identified single nucleotide variants located near COMMD1 that are associated with decreased expression of this gene in humans. Interestingly, these polymorphisms also show a suggestive association signal with ulcerative colitis risk. Consistent with the possibility that genetic variation in COMMD1 expression may predispose to colitis, we find that myeloid deletion of Commd1 leads to more severe colonic inflammation and cancer progression in experimental colitis models. Altogether, the data support the notion that COMMD1 expression in myeloid cells plays an important anti-inflammatory role in physiologic states and human disease. Bone marrow derived macrophages (BMDM) were isolated from two individual wildtype - and two Commd1 knockout mice. Cells from individual mice were splitted and were treated with LPS for 3h, 24h, or, were left untreated. The corresponding 12 cell samples were subjected to total RNA preparation and subsequently used for Single-Color-based Microarray Analysis (Agilent Technologies).
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