Balancing intestinal and systemic inflammation through cell type-specific expression of the aryl hydrocarbon receptor repressor

Brandstätter, Olga; Schanz, Oliver; Vorac, Julia; König, Jessica; Mori, Tetsushi; Maruyama, Toru; Korkowski, Markus; Haarmann‐Stemmann, Thomas; Smolinski, Dorthe von; Schultze, Joachim L.; Abel, Josef; Esser, Charlotte; Takeyama, Haruko; Weighardt, Heike

doi:10.1038/srep26091

Cited by 57 publications

(85 citation statements)

References 72 publications

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“…We showed that LINC00305 overexpression enhances the interaction of LIMR with AHRR, and promotes protein expression as well as nuclear localization of AHRR. AHRR was recently reported to promote inflammation in LPS shock40, and was shown to increase NF-κB activity upon co-transfected with LIMR in the present study. Although AHR expression was also mildly increased upon LINC00305 overexpression, it is largely excluded from the cell nucleus and might be a feedback response to the enhanced NF-κB activity.…”

Section: Discussionsupporting

confidence: 70%

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Long noncoding RNA LINC00305 promotes inflammation by activating the AHRR-NF-κB pathway in human monocytes

Zhang

Wang

Xiong

et al. 2017

Sci Rep

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Accumulating data from genome-wide association studies (GWAS) have provided a collection of novel candidate genes associated with complex diseases, such as atherosclerosis. We identified an atherosclerosis-associated single-nucleotide polymorphism (SNP) located in the intron of the long noncoding RNA (lncRNA) LINC00305 by searching the GWAS database. Although the function of LINC00305 is unknown, we found that LINC00305 expression is enriched in atherosclerotic plaques and monocytes. Overexpression of LINC00305 promoted the expression of inflammation-associated genes in THP-1 cells and reduced the expression of contractile markers in co-cultured human aortic smooth muscle cells (HASMCs). We showed that overexpression of LINC00305 activated nuclear factor-kappa beta (NF-κB) and that inhibition of NF-κB abolished LINC00305-mediated activation of cytokine expression. Mechanistically, LINC00305 interacted with lipocalin-1 interacting membrane receptor (LIMR), enhanced the interaction of LIMR and aryl-hydrocarbon receptor repressor (AHRR), and promoted protein expression as well as nuclear localization of AHRR. Moreover, LINC00305 activated NF-κB exclusively in the presence of LIMR and AHRR. In light of these findings, we propose that LINC00305 promotes monocyte inflammation by facilitating LIMR and AHRR cooperation and the AHRR activation, which eventually activates NF-κB, thereby inducing HASMC phenotype switching.

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Section: Discussionsupporting

confidence: 70%

“…Ahr interacts and cooperates with NF-κB in inflammation regulation, and mainly exhibits an inflammation-suppressive role383940. To evaluate the potential pro-inflammatory role of AHRR, reporter assays were carried out in 293 T cells, and demonstrated that co-transfection of LIMR and AHRR markedly activated NF-κB.…”

Section: Resultsmentioning

confidence: 99%

Long noncoding RNA LINC00305 promotes inflammation by activating the AHRR-NF-κB pathway in human monocytes

Zhang

Wang

Xiong

et al. 2017

Sci Rep

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“…AHRR has been retained in nearly all vertebrate groups (Table 1), suggesting that it has an important physiological function. Recent findings regarding the possible roles of AHRR in the immune system [90,91], reproduction [92,93], and carcinogenesis [94,95] support that notion.…”

Section: Ahr In Deuterostomes: Expansion Through Gene and Genome Dmentioning

confidence: 93%

Diversity as opportunity: Insights from 600 million years of AHR evolution

Hahn

Karchner

Merson

2017

Current Opinion in Toxicology

107

111

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The aryl hydrocarbon receptor (AHR) was for many years of interest only to pharmacologists and toxicologists. However, this protein has fundamental roles in biology that are being revealed through studies in diverse animal species. The AHR is an ancient protein. AHR homologs exist in most major groups of modern bilaterian animals, including deuterostomes (chordates, hemichordates, echinoderms) and the two major clades of protostome invertebrates [ecdysozoans (e.g. arthropods and nematodes) and lophotrochozoans (e.g. molluscs and annelids)]. AHR homologs also have been identified in cnidarians such as the sea anemone Nematostella and in the genome of Trichoplax, a placozoan. Bilaterians, cnidarians, and placozoans form the clade Eumetazoa, whose last common ancestor lived approximately 600 million years ago (MYA). The presence of AHR homologs in modern representatives of all these groups indicates that the original eumetazoan animal possessed an AHR homolog. Studies in invertebrates and vertebrates reveal parallel functions of AHR in the development and function of sensory neural systems, suggesting that these may be ancestral roles. Vertebrate animals are characterized by the expansion and diversification of AHRs, via gene and genome duplications, from the ancestral protoAHR into at least five classes of AHR-like proteins: AHR, AHR1, AHR2, AHR3, and AHRR. The evolution of multiple AHRs in vertebrates coincided with the acquisition of high-affinity binding of halogenated and polynuclear aromatic hydrocarbons and the emergence of adaptive functions involving regulation of xenobiotic-metabolizing enzymes and roles in adaptive immunity. The existence of multiple AHRs may have facilitated subfunction partitioning and specialization of specific AHR types in some taxa. Additional research in diverse model and non-model species will continue to enrich our understanding of AHR and its pleiotropic roles in biology and toxicology.

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“…These drastic increase are mediated (at least in great part) by the Ah receptor (AhR), which, especially in immune cells of the skin (and of the intestine), is counterregulated by the AhR repressor (AhRR) (Brandstätter et al 2016). The concentration of AhR is highest in the spinous and in the granular layers and lowest in the basal layer of the human skin epidermis (Swanson 2004).…”

Section: Xenobiotica-metabolizing Enzymes In the Human Skin Includingmentioning

confidence: 99%

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

2018

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Studies on the metabolic fate of medical drugs, skin care products, cosmetics and other chemicals intentionally or accidently applied to the human skin have become increasingly important in order to ascertain pharmacological effectiveness and to avoid toxicities. The use of freshly excised human skin for experimental investigations meets with ethical and practical limitations. Hence information on xenobiotic-metabolizing enzymes (XME) in the experimental systems available for pertinent studies compared with native human skin has become crucial. This review collects available information of which—taken with great caution because of the still very limited data—the most salient points are: in the skin of all animal species and skin-derived in vitro systems considered in this review cytochrome P450 (CYP)-dependent monooxygenase activities (largely responsible for initiating xenobiotica metabolism in the organ which provides most of the xenobiotica metabolism of the mammalian organism, the liver) are very low to undetectable. Quite likely other oxidative enzymes [e.g. flavin monooxygenase, COX (cooxidation by prostaglandin synthase)] will turn out to be much more important for the oxidative xenobiotic metabolism in the skin. Moreover, conjugating enzyme activities such as glutathione transferases and glucuronosyltransferases are much higher than the oxidative CYP activities. Since these conjugating enzymes are predominantly detoxifying, the skin appears to be predominantly protected against CYP-generated reactive metabolites. The following recommendations for the use of experimental animal species or human skin in vitro models may tentatively be derived from the information available to date: for dermal absorption and for skin irritation esterase activity is of special importance which in pig skin, some human cell lines and reconstructed skin models appears reasonably close to native human skin. With respect to genotoxicity and sensitization reactive-metabolite-reducing XME in primary human keratinocytes and several reconstructed human skin models appear reasonably close to human skin. For a more detailed delineation and discussion of the severe limitations see the Conclusions section in the end of this review.

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Balancing intestinal and systemic inflammation through cell type-specific expression of the aryl hydrocarbon receptor repressor

Cited by 57 publications

References 72 publications

Long noncoding RNA LINC00305 promotes inflammation by activating the AHRR-NF-κB pathway in human monocytes

Long noncoding RNA LINC00305 promotes inflammation by activating the AHRR-NF-κB pathway in human monocytes

Diversity as opportunity: Insights from 600 million years of AHR evolution

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

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