Apoptotic cell–induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans

Shinde, Rahul; Hezaveh, Kebria; Halaby, Marie Jo; Kloetgen, Andreas; Chakravarthy, Ankur; Medina, Tiago da Silva; Deol, Reema; Manion, Kieran; Baglaenko, Yuriy; Eldh, Maria; Lamorte, Sara; Wallace, Drew; Chodisetti, Sathi Babu; Ravishankar, Buvana; Liu, Haiyun; Chaudhary, Kapil; Munn, David H.; Tsirigos, Aristotelis; Madaio, Michael P.; Gabrielsson, Susanne; Touma, Zahi; Wither, Joan E.; Carvalho, Daniel D. De; McGaha, Tracy L.

doi:10.1038/s41590-018-0107-1

Cited by 159 publications

(118 citation statements)

References 49 publications

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“…We observed relatively lower levels of IAA and indoxyl in CRC patients susceptible to anemia, and lower levels of IAcrGly in CRC patients susceptible to HFS. Since both IAA and IAcrGly can activate AHR that exert protective effects on autoimmune inflammation 82 , 83 , 84 , 85 , the urinary levels of which are mediated by tryptophan metabolism and gut microbiota, we speculate that the altered gut microbiota may also be an important factor for the susceptibility to CRAE. In summary, urinal metabolomics is affected by the health condition of individual, including proliferation, differentiation, and inflammation.…”

Section: Discussionmentioning

confidence: 97%

Profiling of polar urine metabolite extracts from Chinese colorectal cancer patients to screen for potential diagnostic and adverse-effect biomarkers

Deng¹,

Yao²,

Chen³

et al. 2020

J. Cancer

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Background: Metabolomics has demonstrated its potential in the early diagnosis, drug safety evaluation and personalized toxicology research of various cancers. Objectives: We aim to screen for potential diagnostic and capecitabine-related adverse effect (CRAE) biomarkers from urinary endogenous metabolites in Chinese colorectal cancer (CRC) patients. Methods: The metabolic profiles of 139 CRC patients and 50 non-neoplastic controls were analyzed using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry. Results: There were 41 metabolites identified between the CRC patients and the non-neoplastic controls, and 19 metabolites were identified between CRC patients with and without CRAE. Based on these identified metabolites, bioinformatic analysis and prediction model construction were completed. Most of these differential metabolites have important roles in cell proliferation and differentiation and the immune system. Based on binary logistic regression, a CRC prediction model, composed of 3-methylhistidine, N-heptanoylglycine, N 1 ,N 12 -diacetylspermine and hippurate, was established, with an area under curve (AUC) of 0.980 (95% CI: 0.953-1.000; sensitivity: 94.3%; specificity: 92.0%) in the training set, and an AUC of 0.968 (95% CI: 0.933-1.000; sensitivity: 89.9%; specificity: 92.0%) in the testing set. In addition, methionine and 4-pyridoxic acid can be combined to predict hand foot syndrome, with an AUC of 0.884; ubiquinone-1 and 4-pyridoxic acid can be combined to predict anemia, with an AUC of 0.889; and 5-acetamidovalerate and 3,4-methylenesebacic acid can be combined to predict neutropenia, with an AUC of 0.882. Conclusion: The profiling of urine polar metabolites has great potential in the early detection of CRC and the prediction of CRAE.

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Section: Discussionmentioning

confidence: 97%

Profiling of polar urine metabolite extracts from Chinese colorectal cancer patients to screen for potential diagnostic and adverse-effect biomarkers

Deng¹,

Yao²,

Chen³

et al. 2020

J. Cancer

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“…The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that was initially recognized as a receptor mediating the pathologic effects of dioxins and other pollutants ( 2 ). Recent studies have identified the molecular functions of AhR in the immune system during steady state and during infection and inflammation ( 3 – 6 ). AhR was shown to be involved in LPS-induced inflammatory gene expression ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Promotes IL-10 Expression in Inflammatory Macrophages Through Src-STAT3 Signaling Pathway

et al. 2018

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The aryl hydrocarbon receptor (AhR) is an important immune regulator with a role in inflammatory response. However, the role of AhR in IL-10 production by inflammatory macrophages is currently unknown. In this study, we investigated LPS-induced IL-10 expression in macrophages from AhR-KO mice and AhR-overexpressing RAW264.7 cells. AhR was highly expressed after LPS stimulation through NF-κB pathway. Loss of AhR resulted in reduced IL-10 expression in LPS-induced macrophages. Moreover, the IL-10 expression was elevated in LPS-induced AhR-overexpressing RAW264.7 cells. Maximal IL-10 expression was dependent on an AhR non-genomic pathway closely related to Src and STAT3. Furthermore, AhR-associated Src activity was responsible for tyrosine phosphorylation of STAT3 and IL-10 expression by inflammatory macrophages. Adoptive transfer of AhR-expressing macrophages protected mice against LPS-induced peritonitis associated with high IL-10 production. In conclusion, we identified the AhR-Src-STAT3-IL-10 signaling pathway as a critical pathway in the immune regulation of inflammatory macrophages, It suggests that AhR may be a potential therapeutic target in immune response.

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“…On the contrary, both AhR silencing and AhR pharmacological inhibition increased mo-Mac while decreasing mo-DC proportions. Interestingly, aged female C57BL/6 mice with a myeloid lineage AhR deletion develop a systemic lupus erythematosus (SLE)-like phenotype with chronic immune system activation and kidney pathology relative to WT mice [48]. Collectively, these findings suggest that Ahr plays a role in the modulation of renal inflammation in 2,8-DHA nephropathy.…”

Section: Discussionmentioning

confidence: 92%

Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease

Makhloufi

Nicolas

McKay

et al. 2020

IJMS

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Cardiovascular complications observed in chronic kidney disease (CKD) are associated with aryl hydrocarbon receptor (AhR) activation by tryptophan-derived uremic toxins—mainly indoxyl sulfate (IS). AhR is a ligand-activated transcription factor originally characterized as a receptor of xenobiotics involved in detoxification. The aim of this study was to determine the role of AhR in a CKD mouse model based on an adenine diet. Wild-type (WT) and AhR−/− mice were fed by alternating an adenine-enriched diet and a regular diet for 6 weeks. Our results showed an increased mortality rate of AhR−/− males. AhR−/− females survived and developed a less severe renal insufficiency that WT mice, reflected by urea, creatinine, and IS measurement in serum. The protective effect was related to a decrease of pro-inflammatory and pro-fibrotic gene expression, an attenuation of tubular injury, and a decrease of 2,8-dihydroxyadenine crystal deposition in the kidneys of AhR−/− mice. These mice expressed low levels of xanthine dehydrogenase, which oxidizes adenine into 2,8-dihydroxyadenine, and low levels of the IS metabolism enzymes. In conclusion, the CKD model of adenine diet is not suitable for AhR knockout mice when studying the role of this transcription factor in cardiovascular complications, as observed in human CKD.

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Apoptotic cell–induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans

Cited by 159 publications

References 49 publications

Profiling of polar urine metabolite extracts from Chinese colorectal cancer patients to screen for potential diagnostic and adverse-effect biomarkers

Profiling of polar urine metabolite extracts from Chinese colorectal cancer patients to screen for potential diagnostic and adverse-effect biomarkers

Aryl Hydrocarbon Receptor Promotes IL-10 Expression in Inflammatory Macrophages Through Src-STAT3 Signaling Pathway

Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease

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