The Environmental Sensor AHR Protects from Inflammatory Damage by Maintaining Intestinal Stem Cell Homeostasis and Barrier Integrity

“Wnt-b-Catenin Signaling The intestinal epithelium continuously renews itself from crypt stem cells that differentiate into short-lived specialized epithelial subtypes (Sato et al., 2009).”

“Since we were not able to maintain Ahr-deficient Lgr5Egfp-Ires-creErt2 reporter mice viable for long enough, we used mice heterozygous for Ahr deletion, which were partially affected.”

“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”

“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”

“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”

“In order to directly investigate the role of AHR in the process of crypt stem cell proliferation and differentiation, we generated colon organoids (Sato and Clevers, 2013).”

“Our results provide evidence that Wnt-b-catenin pathway dysregulation in Ahrdeficient IECs occurred upstream of b-catenin degradation, affecting the response to WNT signals themselves through the expression of the two related E3 ubiquitin ligases (ZNRF3 and RNF43) that degrade the Wnt frizzled receptors (Koo et al., 2…”

“We focused on the tumor suppressors RNF43 and ZNRF3, which are transmembrane E3 ubiquitin ligases expressed in LGR5 stem cells that regulate WNT signals by targeting WNT receptors for degradation in an R-spondin-sensitive manner (Hao et al., 2012; Koo et al., 2012; Tsukiyama et al., 2015).”

“AHR activation induces expression of a family of cytochrome P450 enzymes (CYP1 family), which metabolize AHR ligands, thereby terminating the stimulus (Schmidt and Bradfield, 1996).”

“In the context of intestinal homeostasis, Ahr deficiency has detrimental consequences associated with loss of intraepithelial lymphocytes and ILC3 and absence of IL-22 production (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012).”

“, 2017) and in particular a diet high in fat was proposed to augment intestinal stem cell numbers and— in the context of Apc mutation—promote susceptibility to cancerogenesis (Beyaz et al., 2016).”

“In the context of intestinal homeostasis, Ahr deficiency has detrimental consequences associated with loss of intraepithelial lymphocytes and ILC3 and absence of IL-22 production (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012).”

“In the context of intestinal homeostasis, Ahr deficiency has detrimental consequences associated with loss of intraepithelial lymphocytes and ILC3 and absence of IL-22 production (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012).”

“In the context of intestinal homeostasis, Ahr deficiency has detrimental consequences associated with loss of intraepithelial lymphocytes and ILC3 and absence of IL-22 production (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012).”

“Some of the strongest endogenous AHR ligands are derived from phytochemicals such as indole-3-carbinol (I3C) that is converted to the high-affinity AHR ligand ICZ by exposure to stomach acid (Bjeldanes et al., 1991; Kleman et al., 1994).”

“Dietary AHR Ligands Prevent Tumorigenesis and Restore Regulation of Wnt-b-Catenin Pathway The notion that a diet enriched in green vegetables reduces the risk of cancer formation is widely distributed, although scientific evidence from several clinical trials remains inconsistent (Mayne et al., 2016; Potter and Steinm…”

“Our previous research established an important role of the AHR pathway in IECs as ‘‘gatekeeper’’ for the supply of ligands to intestinal immune cells (Schiering et al., 2017).”

“The impact of nutrition on tumorigenesis is widely documented (Zitvogel et al., 2017) and in particular a diet high in fat was proposed to augment intestinal stem cell numbers and— in the context of Apc mutation—promote susceptibility to cancerogenesis (Beyaz et al.”

“This would explain why such mice expressed elevated levels of IL-6 that can promote malignant progression in colon cancer (West et al., 2015).”

“IL-22 that has also been linked to colon cancer in mice and humans (Jiang et al., 2013; Kryczek et al., 2014) is elevated in VillinCreAhrfl/fl mice, probably due to increased levels of AHR ligands accessible to mucosal immune cells, as Ahr-deficient IECs do not express CYP1A1.”

“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”

“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”

“Aberrant Wnt-b-catenin activation is a hallmark of colorectal cancers, highlighting the importance of this pathway in intestinal homeostasis (Novellasdemunt et al., 2015).”

“There are numerous reports on I3C as a cancer-preventive agent (Dı́az-Dı́az et al., 2016; Kim and Milner, 2005; Weng et al., 2008).”

“An important aspect of AHR activation is the necessity for negative feedback regulation as prolonged stimulation has detrimental effects (Andersson et al., 2002; Mitchell and Elferink, 2009).”

“In agreement with published data on increased levels of b-catenin in Ahr / mice (Kawajiri et al., 2009), both strains of mice with dysregulated AHR in IECs had substantially”

“Dietary AHR Ligands Prevent Tumorigenesis and Restore Regulation of Wnt-b-Catenin Pathway The notion that a diet enriched in green vegetables reduces the risk of cancer formation is widely distributed, although scientific evidence from several clinical trials remains inconsistent (Mayne et al., 2016; Potter and Steinm…”

“There are numerous reports on I3C as a cancer-preventive agent (Dı́az-Dı́az et al., 2016; Kim and Milner, 2005; Weng et al., 2008).”

“rodentium, such as FVB and AKR, express the low-affinity Ahr allele as do mice with a floxed Ahr locus (Walisser et al., 2005) and these are substantially more affected by C.”

“IL-22 that has also been linked to colon cancer in mice and humans (Jiang et al., 2013; Kryczek et al., 2014) is elevated in VillinAhr mice, probably due to increased levels of AHR ligands accessible to mucosal immune cells, as Ahr-deficient IECs do not express CYP1A1.”

“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”

“rodentium is an attaching effacing pathogen that causes IEC apoptosis (Vallance et al., 2003) and necessitates replenishment of damaged IECs for maintenance of barrier integrity and repair processes.”

“In order to accelerate the process of tumorigenesis, we applied the widely used AOM/DSS (dextran sulfate sodium) model in which one dose of AOM was followed by two cycles of DSS.”

“The percentage of viable organoids was determined using OrganoSeg software (Borten et al., 2018).”

“An important aspect of AHR activation is the necessity for negative feedback regulation as prolonged stimulation has detrimental effects (Andersson et al., 2002; Mitchell and Elferink, 2009).”

“We focused on the tumor suppressors RNF43 and ZNRF3, which are transmembrane E3 ubiquitin ligases expressed in LGR5 stem cells that regulate WNT signals by targeting WNT receptors for degradation in an R-spondin-sensitive manner (Hao et al., 2012; Koo et al., 2012; Tsukiyama et al., 2015).”

“The progression from inflammation to tumorigenesis is well established (Sch€ afer and Werner, 2008) and our mice readily developed mixed colon adenomas/adenocarcinomas in the standard AOM/DSS model in line with previous data in global Ahr / mice (Dı́az-Dı́az et al., 2016) or even with the mutagen AOM alone.”

“rodentium infection varies between different strains of mice and susceptible strains are characterized by aberrant R-spondin 2 (RSPO2)-mediated Wnt-b-catenin activation which causes excessive ISC proliferation and poor differentiation into epithelial subtypes (Papapietro et al., 2013).”

“In vitro studies on cell lines proposed that AHR functions as part of an E3 ubiquitin ligase complex that serves to ubiquinate b-catenin and target it for degradation (Luecke-Johansson et al., 2017; Ohtake et al., 2007).”

“Some of the strongest endogenous AHR ligands are derived from phytochemicals such as indole-3-carbinol (I3C) that is converted to the high-affinity AHR ligand ICZ by exposure to stomach acid (Bjeldanes et al., 1991; Kleman et al., 1994).”