Copper Metabolism Domain-Containing 1 Represses Genes That Promote Inflammation and Protects Mice From Colitis and Colitis-Associated Cancer

Abstract

BACKGROUND & AIMS Activation of the transcription factor NFκB has been associated with development of inflammatory bowel disease (IBD). COMMD1, a regulator of various transport pathways, has been shown to limit NFκB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in humans. METHODS We created mice with specific disruption of Commd1 in myeloid cells (Mye-K/O mice); we analyzed immune cell populations and functions and expression of genes regulated by NFκB. 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 (DSS), and colitis-associated cancer was induced by administration of DSS and azoxymethane. We measured levels of COMMD1 mRNA in colon biopsies 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. RESULTS In 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 reduced expression of COMMD1 in colon biopsies 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. CONCLUSIONS Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.

A cell-type-specific role for murine Commd1 in liver inflammation

“…The increased lipid accumulation observed in HFC-fed Commd1 ΔMye mice might therefore be explained by the elevated Tnfα expression in these mice. Our observation of a higher inflammatory tone in the liver of HFC-fed Commd1 ΔMye mice is in line with our recent study [40], in which we showed that myeloid depletion of Commd1 exacerbates dextran sodium sulfate (DSS)-induced colitis and increases the susceptibility to sepsis because it invokes a stronger inflammatory response. Furthermore, Commd1 deficiency in bone-marrow derived myeloid cells selectively altered the expression of LPS-mediated genes, including a subset of genes involved in the immune response, and genes directly regulated by NF-κB [40].…”

“…Our observation of a higher inflammatory tone in the liver of HFC-fed Commd1 ΔMye mice is in line with our recent study [40], in which we showed that myeloid depletion of Commd1 exacerbates dextran sodium sulfate (DSS)-induced colitis and increases the susceptibility to sepsis because it invokes a stronger inflammatory response. Furthermore, Commd1 deficiency in bone-marrow derived myeloid cells selectively altered the expression of LPS-mediated genes, including a subset of genes involved in the immune response, and genes directly regulated by NF-κB [40]. However, these expression data also demonstrated that in addition to NF-κB, myeloid Commd1 also mediates other pathways activated by LPS, either directly or indirectly [40].…”

“…We crossed mice carrying floxed conditional Commd1 alleles with LysM-Cre transgenic mice [23] to specifically ablate Commd1 in the myeloid lineage (Fig. S2A,B) [40]. We fed WT (n=6–7) and Commd1 ΔMye mice (n=6–7) either chow or HFC diet for 12 weeks.…”

“…Furthermore, Commd1 deficiency in bone-marrow derived myeloid cells selectively altered the expression of LPS-mediated genes, including a subset of genes involved in the immune response, and genes directly regulated by NF-κB [40]. However, these expression data also demonstrated that in addition to NF-κB, myeloid Commd1 also mediates other pathways activated by LPS, either directly or indirectly [40]. In addition, the intestinal epithelial-deficient Commd1 mice do not show increased inflammation or any sensitivity difference in DSS-induced colitis, resembling some aspects of the hepatic-specific deficiency that we present here.…”

A novel nano-copper-bearing stainless steel with reduced Cu2+ release only inducing transient foreign body reaction via affecting the activity of NF-κB and Caspase 3

“…30 In addition, some previous studies demonstrated that COMMD1, one of the most frequently studied members of copper ion metabolism gene domain protein family, could effectively restrain the activity of NF-κB, 31,32 thus hinting that copper metabolism disorder might affect the activity of NF-κB pathway. Therefore, we first considered whether the NF-κB pathway had a certain utility in the transient enhanced inflammation caused by such new copper-containing SS after being implanted into the body.…”