A20 controls intestinal homeostasis through cell-specific activities

Vereecke, Lars; Vieira-Silva, Sara; Billiet, Thomas; Es, Johan H. van; Guire, Conor Mc; Slowicka, Karolina; Sze, Mozes; Born, Marise Ph.; Hertogh, Gert De; Clevers, Hans; Raes, Jeroen; Rutgeerts, Paul; Vermeire, Séverine; Beyaert, Rudi; Loo, Geert

doi:10.1038/ncomms6103

Cited by 115 publications

(110 citation statements)

References 66 publications

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“…This was most evident in the distal colon where the inner mucus layer is best developed. This suggests a special mucus niche for this bacterium, something that has also been observed before (Robertson et al, 2005; Vereecke et al, 2014; Belzer et al, 2014). …”

Section: Discussionsupporting

confidence: 80%

Normalization of Host Intestinal Mucus Layers Requires Long-Term Microbial Colonization

Johansson

Jakobsson

Holmén-Larsson

et al. 2015

Cell Host & Microbe

414

340

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SUMMARY The intestinal mucus layer provides a barrier limiting bacterial contact with the underlying epithelium. Mucus structure is shaped by intestinal location and the microbiota. To understand how commensals modulate gut mucus, we examined mucus properties under germ-free (GF) conditions and during microbial colonization. Although the colon mucus structure of GF mice was similar to conventionally raised (Convr) mice, the GF inner mucus layer was penetrable to bacteria-sized beads. During colonization, in which GF mice were gavaged with Convr microbiota, the small intestine mucus required five weeks to be normally detached and colonic inner mucus six weeks to become impenetrable. The composition of the small intestinal microbiota during colonization was similar to Convr donors until three weeks when Bacteroides increased, Firmicutes decreased, and segmented filamentous bacteria became undetectable. These findings highlight the dynamics of mucus layer development and indicate that studies of mature microbe-mucus interactions should be conducted weeks after colonization.

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Section: Discussionsupporting

confidence: 80%

Normalization of Host Intestinal Mucus Layers Requires Long-Term Microbial Colonization

Johansson

Jakobsson

Holmén-Larsson

et al. 2015

Cell Host & Microbe

414

340

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“…This interest is due to the revelation that these regulatory proteins significantly attenuate disease pathogenesis in IBD mouse models. For example, prior studies by our group and others have shown that a diverse group of negative regulatory proteins, including NLRP12, NLRX1, TOLLIP, A20, and GIT2, also function to maintain immune system homeostasis in the gut through the attenuation of hyper-responsive inflammation (Mukherjee and Biswas, 2014, Vereecke et al, 2014, Hammer et al, 2011, Boj et al, 2015, Allen et al, 2012, Zaki et al, 2011, Soares et al, 2014, Singh et al, 2015). Many of these negative regulatory proteins have been found dysregulated in IBD and CRC patients.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M

et al. 2017

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Aberrant inflammation is a hallmark of inflammatory bowel disease (IBD) and colorectal cancer. IRAK-M is a critical negative regulator of TLR signaling and overzealous inflammation. Here we utilize data from human studies and Irak-m−/− mice to elucidate the role of IRAK-M in the modulation of gastrointestinal immune system homeostasis. In human patients, IRAK-M expression is up-regulated during IBD and colorectal cancer. Further functional studies in mice revealed that Irak-m−/− animals are protected against colitis and colitis associated tumorigenesis. Mechanistically, our data revealed that the gastrointestinal immune system of Irak-m−/− mice is highly efficient at eliminating microbial translocation following epithelial barrier damage. This attenuation of pathogenesis is associated with expanded areas of gastrointestinal associated lymphoid tissue (GALT), increased neutrophil migration, and enhanced T-cell recruitment. Further evaluation of Irak-m−/− mice revealed a splice variant that robustly activates NF-κB signaling. Together, these data identify IRAK-M as a potential target for future therapeutic intervention.

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“…24 Moreover, recent study has also shown that mice with the nuclear factor-κB-inducible protein A20 conditional knockout in IECs and myeloid cells (A20 IEC-KO mice) could develop severe colitis because of impaired goblet cells causing reduced mucus. 25 The IECs of A20 IEC-KO mice were found to be sensitive to TNF-induced apoptosis. Thus, A20 possesses a dominant anti-apoptotic effect on IECs, although it could negatively regulate nuclear factor-κB signaling that also plays a role in protecting barrier integrity via inhibiting the apoptosis of IECs.…”

Section: Epithelial Barriermentioning

confidence: 98%

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota

et al. 2015

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The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3+ regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders.

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A20 controls intestinal homeostasis through cell-specific activities

Cited by 115 publications

References 66 publications

Normalization of Host Intestinal Mucus Layers Requires Long-Term Microbial Colonization

Normalization of Host Intestinal Mucus Layers Requires Long-Term Microbial Colonization

Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota

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