Regulated IFN signalling preserves the stemness of intestinal stem cells by restricting differentiation into secretory-cell lineages

Sato, Taku; Ishikawa, Shun; Asano, Jumpei; Yamamoto, Hirona; Fujii, Masayuki; Sato, Toshiro; Yamamoto, Kouhei; Kitagaki, Keisuke; Akashi, Takumi; Okamoto, Ryuichi; Ohteki, Toshiaki

doi:10.1038/s41556-020-0545-5

Cited by 27 publications

(33 citation statements)

References 29 publications

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“…These effects of IFNs on HSCs are considered to be one cause of pancytopenia, a secondary and common complication during infection and autoimmune diseases 29 . We previously and recently reported that uncontrolled physiological IFN signaling reduces the selfrenewal capacity of HSCs and ISCs in Irf2 −/− mice, promoting their forced differentiation into hematopoietic progenitors and secretory progenitors, respectively 13,14 . IFNs promote host defense on one hand.…”

Section: Discussionmentioning

confidence: 95%

“…We obtained C57BL/6J (B6) mice from Japan SLC, Inc.; Villin-Cre transgenic mice, Lgr5-EGFP-Ires-CreERT2 ( Lgr5 ki ) from Jackson Laboratory; Irf2-flox mice were generated as recently described 14 For poly(I:C) (polyinosinic:polycytidylic acid) treatment, mice were injected intraperitoneally with PBS or 2 mg/kg body weight of poly(I:C) for 7 consecutive days. To induce mucosal injury in the colon, mice were given 2% w/v DSS (MP Biochemical, Santa Ana, CA) in drinking water for 5–7 days.…”

Section: Methodsmentioning

confidence: 99%

“…Notably, our group and others previously showed that type I IFNs attenuate the functions of hematopoietic stem cells (HSCs) in mouse bone marrow 12 , 13 . In addition, we have recently showed that regulated IFN-signaling preserves the stemness of small intestinal stem cells (ISCs) by restricting differentiation into secretory-cells 14 .…”

Section: Introductionmentioning

confidence: 99%

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IRF2 maintains the stemness of colonic stem cells by limiting physiological stress from interferon

Minamide

Sato

Nakanishi

et al. 2020

Sci Rep

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The physiological stresses that diminish tissue stem-cell characteristics remain largely unknown. We previously reported that type I interferon (IFN), which is essential for host antiviral responses, is a physiological stressor for hematopoietic stem cells (HSCs) and small intestinal stem cells (ISCs) and that interferon regulatory factor-2 (IRF2), which attenuates IFN signaling, maintains their stemness. Here, using a dextran sodium sulfate (DSS)-induced colitis model, we explore the role of IRF2 in maintaining colonic epithelial stem cells (CoSCs). In mice with a conditional Irf2 deletion in the intestinal epithelium (hereafter Irf2ΔIEC mice), both the number and the organoid-forming potential of CoSCs were markedly reduced. Consistent with this finding, the ability of Irf2ΔIEC mice to regenerate colon epithelium after inducing colitis was severely impaired, independently of microbial dysbiosis. Mechanistically, CoSCs differentiated prematurely into transit-amplifying (TA) cells in Irf2ΔIEC mice, which might explain their low CoSC counts. A similar phenotype was induced in wild-type mice by repeated injections of low doses of poly(I:C), which induces type I IFN. Collectively, we demonstrated that chronic IFN signaling physiologically stresses CoSCs. This study provides new insight into the development of colitis and molecular mechanisms that maintain functional CoSCs throughout life.

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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IRF2 maintains the stemness of colonic stem cells by limiting physiological stress from interferon

Minamide

Sato

Nakanishi

et al. 2020

Sci Rep

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“…Altogether, these results suggest that, following their hyperproliferation induced by impaired β-catenin-NTF interactions, IESCs are subjected to combination of cell-intrinsic (UPR) and environmental (cytokines) stresses, which inhibit their self renewal [34][35][36] . Notably, antigen presentation is intrinsically linked to UPR, as Xbp1 is also a regulator of MHC class II genes 37,38 .…”

Section: Resultsmentioning

confidence: 92%

“…6a). It has recently been shown that T-cellderived TNFα, IFNγ and interleukin 17 (IL-17) inhibit IESC renewal 34 , and that excess interferon-γ signalling induces misdifferentiation towards the secretory fate 35 . Upon restimulation with PMA and ionomycin, we observed a substantial, albeit not significant, increase in TNFα, IFNγ and IL-17 secretion from CD4 + and CD8 + T cells isolated from D164A animals 4d pi (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Differential regulation of β-catenin-mediated transcription via N- and C-terminal co-factors governs identity of murine intestinal epithelial stem cells

et al. 2021

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The homeostasis of the gut epithelium relies upon continuous renewal and proliferation of crypt-resident intestinal epithelial stem cells (IESCs). Wnt/β-catenin signaling is required for IESC maintenance, however, it remains unclear how this pathway selectively governs the identity and proliferative decisions of IESCs. Here, we took advantage of knock-in mice harboring transgenic β-catenin alleles with mutations that specifically impair the recruitment of N- or C-terminal transcriptional co-factors. We show that C-terminally-recruited transcriptional co-factors of β-catenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with β-catenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune β-catenin’s transcriptional output to ensure proper self-renewal and proliferative behaviour of IESCs. Impairment of N-terminal interactions triggers transient hyperproliferation of IESCs, eventually resulting in exhaustion of the self-renewing stem cell pool. IESC mis-differentiation, accompanied by unfolded protein response stress and immune infiltration, results in a process resembling aberrant “villisation” of intestinal crypts. Our data suggest that IESC-specific Wnt/β-catenin output requires selective modulation of gene expression by transcriptional co-factors.

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Low‐Dose Chemotherapy Preferentially Shapes the Ileal Microbiome and Augments the Response to Immune Checkpoint Blockade by Activating AIM2 Inflammasome in Ileal Epithelial Cells

Pu,

Li,

et al. 2024

Advanced Science

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Intervention of the gut microbiome is a promising adjuvant strategy in cancer immunotherapy. Chemotherapeutic agents are recognized for their substantial impacts on the gut microbiome, yet their therapeutic potential as microbiome modulators remains uncertain, due to the complexity of microbiome‐host‐drug interactions. Here, it is showed that low‐dose chemotherapy preferentially shapes the ileal microbiome to augment the extraintestinal immune response to anti‐programmed death‐1 (anti‐PD‐1) therapy without causing intestinal toxicity. Mechanistically, low‐dose chemotherapy causes DNA damage restricted to highly‐proliferative ileal epithelial cells, resulting in the accumulation of cytosolic dsDNA and the activation of the absent in melanoma 2 (AIM2) inflammasome. AIM2‐dependent IL‐18 secretion triggers the interplay between proximal Th1 cells and Paneth cells in ileal crypts, impairing the local antimicrobial host defense and resulting in ileal microbiome change. Intestinal epithelium‐specific knockout of AIM2 in mice significantly attenuates CPT‐11‐caused IL‐18 secretion, Paneth cell dysfunction, and ileal microbiome alteration. Moreover, AIM2 deficiency in mice or antibiotic microbial depletion attenuates chemotherapy‐augmented antitumor responses to anti‐PD1 therapy. Collectively, these findings provide mechanistic insights into how chemotherapy‐induced genomic stress is transduced to gut microbiome change and support the rationale of applying low‐dose chemotherapy as a promising adjuvant strategy in cancer immunotherapy with minimal toxicity.

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Regulated IFN signalling preserves the stemness of intestinal stem cells by restricting differentiation into secretory-cell lineages

Cited by 27 publications

References 29 publications

IRF2 maintains the stemness of colonic stem cells by limiting physiological stress from interferon

IRF2 maintains the stemness of colonic stem cells by limiting physiological stress from interferon

Differential regulation of β-catenin-mediated transcription via N- and C-terminal co-factors governs identity of murine intestinal epithelial stem cells

Low‐Dose Chemotherapy Preferentially Shapes the Ileal Microbiome and Augments the Response to Immune Checkpoint Blockade by Activating AIM2 Inflammasome in Ileal Epithelial Cells

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