FXR mediates ILC-intrinsic responses to intestinal inflammation

Fu, Ting; Li, Yuwenbin; Oh, Tae Gyu; Cayabyab, Fritz; He, Nanhai; Tang, Qin; Coulter, Sally; Truitt, Morgan; Medina, Paul Mark B.; He, Min; Yu, Ruth T.; Atkins, Annette R.; Zheng, Ye; Liddle, Christopher; Downes, Michael; Evans, Ronald M.

doi:10.1073/pnas.2213041119

Cited by 23 publications

(12 citation statements)

References 56 publications

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“…LCA is a ligand not only for VDR but also for other bile acid receptors, such as FXR, PXR, and TGR5 [ 1 ]. Because the activation of FXR, PXR and TGR5 can suppress DSS-induced colitis [ 41 , 42 , 43 , 44 ], the effect of LCA on inflammatory cytokine expression may be mediated by these receptors. Because VDR is necessary for the effect of LCA on DAI scores and histological injury ( Figure 3 ), VDR-mediated LCA signaling plays a main role in the protection against colitis.…”

Section: Discussionmentioning

confidence: 99%

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Vitamin D Receptor Mediates Attenuating Effect of Lithocholic Acid on Dextran Sulfate Sodium Induced Colitis in Mice

Kubota

Ishizawa

Kodama

et al. 2023

IJMS

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Bile acids are major components of bile; they emulsify dietary lipids for efficient digestion and absorption and act as signaling molecules that activate nuclear and membrane receptors. The vitamin D receptor (VDR) is a receptor for the active form of vitamin D and lithocholic acid (LCA), a secondary bile acid produced by the intestinal microflora. Unlike other bile acids that enter the enterohepatic circulation, LCA is poorly absorbed in the intestine. Although vitamin D signaling regulates various physiological functions, including calcium metabolism and inflammation/immunity, LCA signaling remains largely unknown. In this study, we investigated the effect of the oral administration of LCA on colitis in a mouse model using dextran sulfate sodium (DSS). Oral LCA decreased the disease activity of colitis in the early phase, which is a phenotype associated with the suppression of histological injury, such as inflammatory cell infiltration and goblet cell loss. These protective effects of LCA were abolished in VDR-deleted mice. LCA decreased the expression of inflammatory cytokine genes, but this effect was at least partly observed in VDR-deleted mice. The pharmacological effect of LCA on colitis was not associated with hypercalcemia, an adverse effect induced by vitamin D compounds. Therefore, LCA suppresses DSS-induced intestinal injury in its action as a VDR ligand.

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Section: Discussionmentioning

confidence: 99%

“…The effect of oral CDCA administration likely occurs through conversion to LCA and VDR activation. However, CDCA is a potent FXR agonist [ 15 ], and FXR activation suppresses DSS-induced colitis [ 41 , 44 ]. In addition to FXR agonist activity, CDCA activates the NLRP3 inflammasome and exacerbates hepatic inflammation in mice [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Receptor Mediates Attenuating Effect of Lithocholic Acid on Dextran Sulfate Sodium Induced Colitis in Mice

Kubota

Ishizawa

Kodama

et al. 2023

IJMS

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“…The expression of IL-1β, IL-6, COX-2, TNF-α, and ICAM was repressed by Rc. Specifically, the researchers focused on the function of the farnesoid x receptor (FXR), a nuclear receptor activated by bile acids, in the inflammatory response of the intestine [ 138 ]. The mRNA level of FXR as well as ZO-1 and claudin-1 was enhanced with Rc treatment in DSS-induced mice.…”

Section: Pharmacological Activities Of Ginsenosides On Inflammatory D...mentioning

confidence: 99%

Ginsenosides from Panax ginseng as Key Modulators of NF-κB Signaling Are Powerful Anti-Inflammatory and Anticancer Agents

Jang

Hwang

Cho

2023

IJMS

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Nuclear factor kappa B (NF-κB) signaling pathways progress inflammation and immune cell differentiation in the host immune response; however, the uncontrollable stimulation of NF-κB signaling is responsible for several inflammatory illnesses regardless of whether the conditions are acute or chronic. Innate immune cells, such as macrophages, microglia, and Kupffer cells, secrete pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, via the activation of NF-κB subunits, which may lead to the damage of normal cells, including neurons, cardiomyocytes, hepatocytes, and alveolar cells. This results in the occurrence of neurodegenerative disorders, cardiac infarction, or liver injury, which may eventually lead to systemic inflammation or cancer. Recently, ginsenosides from Panax ginseng, a historical herbal plant used in East Asia, have been used as possible options for curing inflammatory diseases. All of the ginsenosides tested target different steps of the NF-κB signaling pathway, ameliorating the symptoms of severe illnesses. Moreover, ginsenosides inhibit the NF-κB-mediated activation of cancer metastasis and immune resistance, significantly attenuating the expression of MMPs, Snail, Slug, TWIST1, and PD-L1. This review introduces current studies on the therapeutic efficacy of ginsenosides in alleviating NF-κB responses and emphasizes the critical role of ginsenosides in severe inflammatory diseases as well as cancers.

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“…Further, OCA, also known as INT-747, reduces proinflammatory cytokine secretion in activated mononuclear cells and monocytes derived from inflammatory bowel disease (IBD) patients (22). Notably, murine models of whole-body FXR loss demonstrate an enhanced inflammatory phenotype following DSS treatment with increased innate lymphoid cell presence within the damaged intestine and increased inflammatory cytokine expression (50). Similarly, inhibition of ileal FXR by P. distasonis improves hepatic fibrosis in mice fed methionine and choline deficient diet (51).…”

Section: Fxr Function In Diseasementioning

confidence: 99%

“…Similarly, inhibition of ileal FXR by P. distasonis improves hepatic fibrosis in mice fed methionine and choline deficient diet (51). Prophylactic FXR activation in the intestine, with tissue-specific FXR agonist fexaramine, prevents DSS-induced intestinal villi damage, serum interleukin 17 (IL-17) secretion, and immune cell infiltration of the intestine (50).…”

Section: Fxr Function In Diseasementioning

confidence: 99%

FXR Friend-ChIPs in the Enterohepatic System

et al. 2023

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Chronic liver diseases encompass a wide spectrum of hepatic maladies that often result in cholestasis or altered bile acid secretion and regulation. Incidence and cost of care for many chronic liver diseases are rising in the US with few Food and Drug Administration-approved drugs available for patient treatment. Farnesoid X receptor (FXR) is the master regulator of bile acid homeostasis with an important role in lipid and glucose metabolism and inflammation. FXR has served as an attractive target for management of cholestasis and fibrosis; however, global FXR agonism results in adverse effects in liver disease patients, severely affecting quality of life. In this review, we highlight seminal studies and recent updates on the FXR proteome and identify gaps in knowledge that are essential for tissue specific FXR modulation. In conclusion, one of the greatest unmet needs in the field is understanding the underlying mechanism of intestinal versus hepatic FXR function.

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FXR mediates ILC-intrinsic responses to intestinal inflammation

Cited by 23 publications

References 56 publications

Vitamin D Receptor Mediates Attenuating Effect of Lithocholic Acid on Dextran Sulfate Sodium Induced Colitis in Mice

Vitamin D Receptor Mediates Attenuating Effect of Lithocholic Acid on Dextran Sulfate Sodium Induced Colitis in Mice

Ginsenosides from Panax ginseng as Key Modulators of NF-κB Signaling Are Powerful Anti-Inflammatory and Anticancer Agents

FXR Friend-ChIPs in the Enterohepatic System

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