Analysis of Cdcs1 colitogenic effects in the hematopoietic compartment reveals distinct microbiome interaction and a new subcongenic interval active in T cells

Bruesch, Inga; Meier, Pascal; Vital, Marius; Pieper, Dietmar H.; Selke, Kristin; Böhlen, Sebastian; Basic, Marijana; Meier, Martin; Glage, Silke; Hundrieser, J.; Wedekind, Dirk; Büettner, Manuela

doi:10.1038/s41385-019-0133-9

Cited by 5 publications

(7 citation statements)

References 57 publications

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“…Our group previously described Alpk1 as a Cdcs1 locus candidate gene for IL10 deficiency-induced colitis severity in mice [4] and recently excluded a T cell-dependent role for ALPK1 in colitis progression [5]. Our present study shows an influence of Alpk1 on epithelial barrier components in response to EcN and therefore perhaps to tolerance to commensal bacteria.…”

supporting

confidence: 55%

“…Using the Il10 -/mouse model and quantitative trait locus (QTL) analyses, several studies have identified genetic loci associated with susceptibility to IBD. These studies revealed ten cytokine deficiency-induced colitis susceptibility (Cdcs) loci and candidate genes with a potential influence on colitis onset [4][5][6][7][8][9]. One of these genes is Cd14 (Cluster of differentiation 14) in the Cdcs6 locus located on chromosome 18 [7].…”

Section: Introductionmentioning

confidence: 99%

“…Another candidate gene revealed by these QTL studies is Alpk1 (alpha-protein kinase 1) which is located on chromosome 3 in the Cdcs1 locus [4,5]. Knockout of the Alpk1 gene in mice was recently shown to lead to severe colitis when infected with Helicobacter hepaticus [13].…”

Section: Introductionmentioning

confidence: 99%

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CD14 and ALPK1 Affect Expression of Tight Junction Components and Proinflammatory Mediators upon Bacterial Stimulation in a Colonic 3D Organoid Model

Brooks

Bruegge

Boyle

et al. 2020

Stem Cells International

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Cd14 and Alpk1 both encode pathogen recognition receptors and are known candidate genes for affecting severity in inflammatory bowel diseases. CD14 acts as a coreceptor for bacterial lipopolysaccharide (LPS), while ALPK1 senses ADP-D-glycero-beta-D-manno-heptose, a metabolic intermediate of LPS biosynthesis. Intestinal barrier integrity can be influenced by CD14, whereas to date, the role of ALPK1 in maintaining barrier function remains unknown. We used colon-derived 3D organoids, first characterised for growth, proliferation, stem cell markers, and expression of tight junction (TJ) components using qPCR and immunohistochemistry. They showed characteristic crypt stem cells, apical shedding of dead cells, and TJ formation. Afterwards, organoids of different genotypes (WT, Il10-/-, Cd14-/-, and Alpk1-/-) were then stimulated with either LPS or Escherichia coli Nissle 1917 (EcN). Gene expression and protein levels of cytokines and TJ components were analysed. WT organoids increased expression of Tnfα and tight junction components. Cd14-/- organoids expressed significantly less Tnfα and Ocln after LPS stimulation than WT organoids but reacted similarly to WT organoids after EcN stimulation. In contrast, compared to WT, Alpk1-/- organoids showed decreased expression of different TJ and cytokine genes in response to EcN but not LPS. However, Western blotting revealed an effect of ALPK1 on TJ protein levels. These findings demonstrate that Cd14, but not Alpk1, alters the response to LPS stimulation in colonic epithelial cells, whereas Alpk1 is involved in the response upon bacterial challenge.

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supporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

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CD14 and ALPK1 Affect Expression of Tight Junction Components and Proinflammatory Mediators upon Bacterial Stimulation in a Colonic 3D Organoid Model

Brooks

Bruegge

Boyle

et al. 2020

Stem Cells International

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“…Skin tissue from IL-10 deficient mice on the C57BL/6 background and C57BL/6 wild-type controls was prepared from 6-20 week old female and male donor mice. Il-10 -/mice and co-housed wild-type control mice were bred at the House of Experimental Therapy (HET) of the University of Bonn [74] and in the animal facility of Hannover Medical School [75] under SPF conditions. Female 10-13 months old WBB6F1 Kit W/Wv and Kit +/+ littermates were kindly provided by Hans-Reimer Rodewald, DKFZ, Heidelberg.…”

Section: Animalsmentioning

confidence: 99%

AHR Signaling Dampens Inflammatory Signature in Neonatal Skin γδ T Cells

Merches

Schiavi

Weighardt

et al. 2020

IJMS

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Background Aryl hydrocarbon receptor (AHR)-deficient mice do not support the expansion of dendritic epidermal T cells (DETC), a resident immune cell population in the murine epidermis, which immigrates from the fetal thymus to the skin around birth. Material and Methods In order to identify the gene expression changes underlying the DETC disappearance in AHR-deficient mice, we analyzed microarray RNA-profiles of DETC, sorted from the skin of two-week-old AHR-deficient mice and their heterozygous littermates. In vitro studies were done for verification, and IL-10, AHR repressor (AHRR), and c-Kit deficient mice analyzed for DETC frequency. Results We identified 434 annotated differentially expressed genes. Gene set enrichment analysis demonstrated that the expression of genes related to proliferation, ion homeostasis and morphology differed between the two mouse genotypes. Importantly, with 1767 pathways the cluster-group “inflammation” contained the majority of AHR-dependently regulated pathways. The most abundant cluster of differentially expressed genes was “inflammation.” DETC of AHR-deficient mice were inflammatory active and had altered calcium and F-actin levels. Extending the study to the AHRR, an enigmatic modulator of AHR-activity, we found approximately 50% less DETC in AHRR-deficient mice than in wild-type-littermates. Conclusion AHR-signaling in DETC dampens their inflammatory default potential and supports their homeostasis in the skin.

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“…However, the intestinal microbiota was shown to be essential for disease development, as GF Il10 −/− mice do not develop colitis (18, 19). The composition of the intestinal microbiota can alter colitis severity of Il10 −/− mice (20, 21). Previously, we have shown that MNV infection triggers colitis in Il10 −/− mice in a microbiota-dependent manner (22).…”

Section: Introductionmentioning

confidence: 99%

Composition of the Intestinal Microbiota Determines the Outcome of Virus-Triggered Colitis in Mice

et al. 2019

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The intestinal microbiota is a complex ecosystem implicated in host health and disease. Inflammatory bowel disease (IBD) is a multifactorial chronic disorder of the gastrointestinal mucosa. Even though the exact mechanisms are still unknown, the intestinal microbiota is crucial in IBD development. We previously showed that murine norovirus (MNV) induces colitis in the Il10 -deficient ( Il10 −/− ) mouse model of IBD in a microbiota-dependent manner. Thus, in this study we analyzed whether distinct minimal bacterial consortia influence the outcome of MNV-triggered colitis in Il10 −/− mice. Gnotobiotic Il10 −/− mice associated with Oligo-Mouse-Microbiota 12 (OMM 12 ) or Altered Schaedler Flora (ASF) developed little to no inflammatory lesions in the colon and cecum. MNV infection exacerbated colitis severity only in ASF-colonized mice, but not in those associated with OMM 12 . Four weeks after MNV infection, inflammatory lesions in ASF-colonized Il10 −/− mice were characterized by epithelial hyperplasia, infiltration of inflammatory cells, and increased barrier permeability. Co-colonization of ASF-colonized Il10 −/− mice with segmented filamentous bacteria (SFB) abolished MNV-induced colitis, whereas histopathological scores in SFB-OMM 12 -co-colonized mice stayed unchanged. Moreover, SFB only colonized mice associated with ASF. The SFB-mediated protective effects in ASF-colonized mice involved enhanced activation of intestinal barrier defense mechanisms and mucosal immune responses in the chronic and acute phase of MNV infection. SFB colonization strengthened intestinal barrier function by increasing expression of tight junction proteins, antimicrobial peptides and mucus. Furthermore, SFB colonization enhanced the expression of pro-inflammatory cytokines such as Tnf α, Il1 β, and Il12a , as well as the expression of the regulatory cytokine Tgf β. Altogether, our results showed that MNV-triggered colitis depends on the microbial context.

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Analysis of Cdcs1 colitogenic effects in the hematopoietic compartment reveals distinct microbiome interaction and a new subcongenic interval active in T cells

Cited by 5 publications

References 57 publications

CD14 and ALPK1 Affect Expression of Tight Junction Components and Proinflammatory Mediators upon Bacterial Stimulation in a Colonic 3D Organoid Model

CD14 and ALPK1 Affect Expression of Tight Junction Components and Proinflammatory Mediators upon Bacterial Stimulation in a Colonic 3D Organoid Model

AHR Signaling Dampens Inflammatory Signature in Neonatal Skin γδ T Cells

Composition of the Intestinal Microbiota Determines the Outcome of Virus-Triggered Colitis in Mice

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