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ROR? is crucial for attenuated inflammatory response to maintain intestinal homeostasis.

ABSTRACT: Retinoic acid-related orphan receptor ? (ROR?) functions as a transcription factor for various biological processes, including circadian rhythm, cancer, and metabolism. Here, we generate intestinal epithelial cell (IEC)-specific ROR?-deficient (ROR??IEC) mice and find that ROR? is crucial for maintaining intestinal homeostasis by attenuating nuclear factor ?B (NF-?B) transcriptional activity. ROR??IEC mice exhibit excessive intestinal inflammation and highly activated inflammatory responses in the dextran sulfate sodium (DSS) mouse colitis model. Transcriptome analysis reveals that deletion of ROR? leads to up-regulation of NF-?B target genes in IECs. Chromatin immunoprecipitation analysis reveals corecruitment of ROR? and histone deacetylase 3 (HDAC3) on NF-?B target promoters and subsequent dismissal of CREB binding protein (CBP) and bromodomain-containing protein 4 (BRD4) for transcriptional repression. Together, we demonstrate that ROR?/HDAC3-mediated attenuation of NF-?B signaling controls the balance of inflammatory responses, and therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of chronic inflammatory diseases, including inflammatory bowel disease (IBD).

SUBMITTER: Oh SK

PROVIDER: S-EPMC6800319 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis.

Oh Se Kyu SK Kim Dongha D Kim Kyeongkyu K Boo Kyungjin K Yu Young Suk YS Kim Ik Soo IS Jeon Yoon Y Im Sun-Kyoung SK Lee Su-Hyung SH Lee Ji Min JM Ko Younhee Y Lee Ho H Park Daechan D Fang Sungsoon S Baek Sung Hee SH

Proceedings of the National Academy of Sciences of the United States of America 20190930 42

Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, cancer, and metabolism. Here, we generate intestinal epithelial cell (IEC)-specific RORα-deficient (RORα<sup>ΔIEC</sup>) mice and find that RORα is crucial for maintaining intestinal homeostasis by attenuating nuclear factor κB (NF-κB) transcriptional activity. RORα<sup>ΔIEC</sup> mice exhibit excessive intestinal inflammation and highly activated infla ...[more]

PMID: 31570593

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Project description:BackgroundLactobacillus reuteri strains are widely used as probiotics to prevent and treat inflammatory bowel disease by modulating the host's immune system. However, the underlying mechanisms by which they communicate with the host have not been clearly understood. Bacterial extracellular vesicles (EVs) have been considered as important mediators of host-pathogen interactions, but their potential role in commensals-host crosstalk has not been widely studied. Here, we investigated the regulatory actions of EVs produced by L. reuteri BBC3, a gut-associated commensal bacterium of Black-Bone chicken, in the development of lipopolysaccharide (LPS)-induced intestinal inflammation in a chicken model using both in vivo and in vitro experiments.ResultsL. reuteri BBC3 produced nano-scale membrane vesicles with the size range of 60-250 nm. Biochemical and proteomic analyses showed that L. reuteri BBC3-derived EVs (LrEVs) carried DNA, RNA and several bioactive proteins previously described as mediators of other probiotics' beneficial effects such as glucosyltransferase, serine protease and elongation factor Tu. In vivo broiler experiments showed that administration of LrEVs exerted similar effects as L. reuteri BBC3 in attenuating LPS-induced inflammation by improving growth performance, reducing mortality and decreasing intestinal injury. LrEVs suppressed the LPS-induced expression of pro-inflammatory genes (TNF-α, IL-1β, IL-6, IL-17 and IL-8), and improved the expression of anti-inflammatory genes (IL-10 and TGF-β) in the jejunum. LrEVs could be internalized by chicken macrophages. In vitro pretreatment with LrEVs reduced the gene expression of TNF-α, IL-1β and IL-6 by suppressing the NF-κB activity, and enhanced the gene expression of IL-10 and TGF-β in LPS-activated chicken macrophages. Additionally, LrEVs could inhibit Th1- and Th17-mediated inflammatory responses and enhance the immunoregulatory cells-mediated immunosuppression in splenic lymphocytes of LPS-challenged chickens through the activation of macrophages. Finally, we revealed that the reduced content of both vesicular proteins and nucleic acids attenuated the suppression of LrEVs on LPS-induced inflammatory responses in ex vivo experiments, suggesting that they are essential for the LrEVs-mediated immunoregulation.ConclusionsWe revealed that LrEVs participated in maintaining intestinal immune homeostasis against LPS-induced inflammatory responses in a chicken model. Our findings provide mechanistic insight into how commensal and probiotic Lactobacillus species modulate the host's immune system in pathogens-induced inflammation.

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ROR? is crucial for attenuated inflammatory response to maintain intestinal homeostasis.

Publications

RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis.

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