Genistein protects against DSS-induced colitis by inhibiting NLRP3 inflammasome via TGR5-cAMP signaling

Chen, Yu; Le, Thi Ha; Du, Qianming; Zhao, Zheng; Liu, Yunxin; Zou, Jianjun; Hua, Weiwei; Liu, Chao; Zhu, Yubing

doi:10.1016/j.intimp.2019.01.021

Cited by 63 publications

(32 citation statements)

References 42 publications

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“…105 Activation of the cAMP-PKA signaling pathway is linked to inhibition of NLRP3 inflammasome activity through enhancement of K63-linked ubiquitination of NLRP3. 233 Genistein-mediated anti-inflammasome activity is mediated through TGF5-cAMP signaling via increased intracellular cAMP levels 234 Foxp1 was reported to have a negative regulatory function on endothelial NLRP3 inflammasome activation, acting as a gatekeeper of vessel inflammation. 235 Endothelial Foxp1 is regulated by Krüppel-like factor 2 (Klf2) and further regulates NLRP3 inflammasome activation through direct regulation of endothelial inflammasome components, including NLRP3 and caspase-1.…”

Section: Dual Regulatory Mechanisms Controlling the Nlrp3 Inflammasomementioning

confidence: 99%

An update on the regulatory mechanisms of NLRP3 inflammasome activation

et al. 2021

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The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex involved in the release of mature interleukin-1β and triggering of pyroptosis, which is of paramount importance in a variety of physiological and pathological conditions. Over the past decade, considerable advances have been made in elucidating the molecular mechanisms underlying the priming/licensing (Signal 1) and assembly (Signal 2) involved in NLRP3 inflammasome activation. Recently, a number of studies have indicated that the priming/licensing step is regulated by complicated mechanisms at both the transcriptional and posttranslational levels. In this review, we discuss the current understanding of the mechanistic details of NLRP3 inflammasome activation with a particular emphasis on protein-protein interactions, posttranslational modifications, and spatiotemporal regulation of the NLRP3 inflammasome machinery. We also present a detailed summary of multiple positive and/or negative regulatory pathways providing upstream signals that culminate in NLRP3 inflammasome complex assembly. A better understanding of the molecular mechanisms underlying NLRP3 inflammasome activation will provide opportunities for the development of methods for the prevention and treatment of NLRP3 inflammasome-related diseases.

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Section: Dual Regulatory Mechanisms Controlling the Nlrp3 Inflammasomementioning

confidence: 99%

An update on the regulatory mechanisms of NLRP3 inflammasome activation

et al. 2021

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“…Like FXR, GPBAR1 also exerts a counter-regulatory effects on the activation of the NLPR3 inflammasome [ 50 , 53 ]. Activation of GPBAR1 by secondary bile acid DCA and LCA cause a GPBAR1-cAMP-PKA-dependent ubiquitination of NLRP3, thus inhibiting its activation [ 50 , 53 , 62 ].…”

Section: Bile Acids Activated Receptors (Bars) and Intestinal Immunitymentioning

confidence: 99%

Bile Acids Activated Receptors in Inflammatory Bowel Disease

Biagioli

Marchianò

Carino

et al. 2021

Cells

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Once known exclusively for their role in nutrients absorption, bile acids have emerged as signaling molecules, generated from cholesterol breakdown, acting on several immune cells by activating a variety of receptors including the G protein-coupled bile acid receptor 1 (GPABR1 or TGR5), the Farnesoid-X-receptor (FXR) and, as recently discovered, the retinoid-related orphan receptors (ROR)γt. GPBAR1, FXR, and RORγt are highly expressed in cells of the innate and adaptive immune system (i.e., dendritic cells (DCs), macrophages, innate lymphoid 3 cells (ILC3s), and T helper 17 (Th17) lymphocytes) and plays an important role in regulating intestinal and liver immunity, highlighting a role for various bile acid species in regulating immune responses to intestinal microbial antigens. While primary bile acids are generated from the cholesterol breakdown secondary bile acids, the GPBAR1 ligands, and oxo-bile acids derivatives, the RORγt ligands, are generated by the intestinal microbiota, highlighting the potential of these bile acids in mediating the chemical communication between the intestinal microbiota and the host. Changes in intestinal microbiota, dysbiosis, alter the composition of the bile acid pool, promoting the activation of the immune system and development of chronic inflammation. In this review, we focus on the molecular mechanisms by which an altered bile acid signaling promotes intestinal inflammation.

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“…Such FXR-independent effect of bile acid on NLRP3 inflammasome may be mediated by the membrane receptor Takeda G coupled Receptor 5 (TGR5), another bile acid receptor. Indeed, treatment of BMDM with bile acids suppresses LPS/Nigericin-mediated NLRP3 activation in a TGR5-cAMP-PKA dependent by inducing NLRP3 ubiquitination and phosphorylation (137)(138)(139)(140).…”

Section: Nuclear Receptors Regulate the Nlrp3 Activation Stepmentioning

confidence: 99%

Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway

Duez

Pourcet

2021

Front. Endocrinol.

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The innate immune system is the first line of defense specialized in the clearing of invaders whether foreign elements like microbes or self-elements that accumulate abnormally including cellular debris. Inflammasomes are master regulators of the innate immune system, especially in macrophages, and are key sensors involved in maintaining cellular health in response to cytolytic pathogens or stress signals. Inflammasomes are cytoplasmic complexes typically composed of a sensor molecule such as NOD-Like Receptors (NLRs), an adaptor protein including ASC and an effector protein such as caspase 1. Upon stimulation, inflammasome complex components associate to promote the cleavage of the pro-caspase 1 into active caspase-1 and the subsequent activation of pro-inflammatory cytokines including IL-18 and IL-1β. Deficiency or overactivation of such important sensors leads to critical diseases including Alzheimer diseases, chronic inflammatory diseases, cancers, acute liver diseases, and cardiometabolic diseases. Inflammasomes are tightly controlled by a two-step activation regulatory process consisting in a priming step, which activates the transcription of inflammasome components, and an activation step which leads to the inflammasome complex formation and the subsequent cleavage of pro-IL1 cytokines. Apart from the NF-κB pathway, nuclear receptors have recently been proposed as additional regulators of this pathway. This review will discuss the role of nuclear receptors in the control of the NLRP3 inflammasome and the putative beneficial effect of new modulators of inflammasomes in the treatment of inflammatory diseases including colitis, fulminant hepatitis, cardiac ischemia–reperfusion and brain diseases.

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Genistein protects against DSS-induced colitis by inhibiting NLRP3 inflammasome via TGR5-cAMP signaling

Cited by 63 publications

References 42 publications

An update on the regulatory mechanisms of NLRP3 inflammasome activation

An update on the regulatory mechanisms of NLRP3 inflammasome activation

Bile Acids Activated Receptors in Inflammatory Bowel Disease

Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway

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