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Regulation of S100A8 Stability by RNF5 in Intestinal Epithelial Cells Determines Intestinal Inflammation and Severity of Colitis.

ABSTRACT: Inflammatory bowel disease (IBD) is prevalent, but the mechanisms underlying disease development remain elusive. We identify a role for the E3 ubiquitin ligase RNF5 in IBD. Intestinal epithelial cells (IECs) express a high level of RNF5, while the colon of Rnf5-/- mice exhibits activated dendritic cells and intrinsic inflammation. Rnf5-/- mice exhibit severe acute colitis following dextran sodium sulfate (DSS) treatment. S100A8 is identified as an RNF5 substrate, resulting in S100A8 ubiquitination and proteasomal-dependent degradation that is attenuated upon inflammatory stimuli. Loss of RNF5 from IECs leads to enhanced S100A8 secretion, which induces mucosal CD4+ T cells, resulting in Th1 pro-inflammatory responses. Administration of S100A8-neutralizing antibodies to DSS-treated Rnf5-/- mice attenuates acute colitis development and increases survival. An inverse correlation between RNF5 and S100A8 protein expression in IECs of IBD patients coincides with disease severity. Collectively, RNF5-mediated regulation of S100A8 stability in IECs is required for the maintenance of intestinal homeostasis.

SUBMITTER: Fujita Y

PROVIDER: S-EPMC6185744 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Regulation of S100A8 Stability by RNF5 in Intestinal Epithelial Cells Determines Intestinal Inflammation and Severity of Colitis.

Fujita Yu Y Khateb Ali A Li Yan Y Tinoco Roberto R Zhang Tongwu T Bar-Yoseph Haggai H Tam Miguel A MA Chowers Yehuda Y Sabo Edmond E Gerassy-Vainberg Shiran S Starosvetsky Elina E James Brian B Brown Kevin K Shen-Orr Shai S SS Bradley Linda M LM Tessier Philippe A PA Ronai Ze'ev A ZA

Cell reports 20180901 12

Inflammatory bowel disease (IBD) is prevalent, but the mechanisms underlying disease development remain elusive. We identify a role for the E3 ubiquitin ligase RNF5 in IBD. Intestinal epithelial cells (IECs) express a high level of RNF5, while the colon of Rnf5<sup>-/-</sup> mice exhibits activated dendritic cells and intrinsic inflammation. Rnf5<sup>-/-</sup> mice exhibit severe acute colitis following dextran sodium sulfate (DSS) treatment. S100A8 is identified as an RNF5 substrate, resulting ...[more]

PMID: 30232010

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Project description:Background & aimsIntestinal epithelial cells (IECs) provide a barrier that separates the mucosal immune system from the luminal microbiota. IECs constitutively express low levels of major histocompatibility complex (MHC) class II proteins, which are upregulated upon exposure to interferon gamma. We investigated the effects of deleting MHCII proteins specifically in mice with infectious, dextran sodium sulfate (DSS)-, and T-cell-induced colitis.MethodsWe disrupted the histocompatibility 2, class II antigen A, beta 1 gene (H2-Ab1) in IECs of C57BL/6 mice (I-AbΔIEC) or Rag1-/- mice (Rag1-/-I-AbΔIEC); we used I-AbWT mice as controls. Colitis was induced by administration of DSS, transfer of CD4+CD45RBhi T cells, or infection with Citrobacter rodentium. Colon tissues were collected and analyzed by histology, immunofluorescence, xMAP, and reverse-transcription polymerase chain reaction and organoids were generated. Microbiota (total and immunoglobulin [Ig]A-coated) in intestinal samples were analyzed by16S amplicon profiling. IgA+CD138+ plasma cells from Peyer's patches and lamina propria were analyzed by flow cytometry and IgA repertoire was determined by next-generation sequencing.ResultsMice with IEC-specific loss of MHCII (I-AbΔIEC mice) developed less severe DSS- or T-cell transfer-induced colitis than control mice. Intestinal tissues from I-AbΔIEC mice had a lower proportion of IgA-coated bacteria compared with control mice, and a reduced luminal concentration of secretory IgA (SIgA) following infection with C rodentium. There was no significant difference in the mucosal IgA repertoire of I-AbΔIEC vs control mice, but opsonization of cultured C rodentium by SIgA isolated from I-AbΔIEC mice was 50% lower than that of SIgA from mAbWT mice. Fifty percent of I-AbΔIEC mice died after infection with C rodentium, compared with none of the control mice. We observed a transient but significant expansion of the pathogen in the feces of I-AbΔIEC mice compared with I-AbWT mice.ConclusionsIn mice with DSS or T-cell-induced colitis, loss of MHCII from IECs reduces but does not eliminate mucosal inflammation. However, in mice with C rodentium-induced colitis, loss of MHCII reduces bacterial clearance by decreasing binding of IgA to commensal and pathogenic bacteria.

Dataset Information

Regulation of S100A8 Stability by RNF5 in Intestinal Epithelial Cells Determines Intestinal Inflammation and Severity of Colitis.

Publications

Regulation of S100A8 Stability by RNF5 in Intestinal Epithelial Cells Determines Intestinal Inflammation and Severity of Colitis.

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