NLRP3 inflammasome priming and activation in cholestatic liver injury via the sphingosine 1-phosphate/S1P receptor 2/Gα(12/13)/MAPK signaling pathway

Hou, Lei; Zhang, Zhi; Yang, Le; Chang, Na; Zhao, Xinhao; Zhou, Xuan; Yang, Lin; Li, Liying

doi:10.1007/s00109-020-02032-4

Cited by 34 publications

(34 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the priming event, the current study demonstrated that S1P 2 was responsible for S1P-driven NLRP3 inflammasome activation in LPS-primed BMDMs. The currently identified role of S1P 2 in the regulation of NLRP3 activity is supported by recent studies [23,24]. Suppressing S1P 2 activity with JTE013 treatment attenuated NLRP3 priming and NLPR3 inflammasome activation in S1P-treated BMMs in vitro and bile duct ligation-induced cholestatic liver injury in vivo [23,24].…”

Section: Discussionmentioning

confidence: 81%

“…The currently identified role of S1P 2 in the regulation of NLRP3 activity is supported by recent studies [23,24]. Suppressing S1P 2 activity with JTE013 treatment attenuated NLRP3 priming and NLPR3 inflammasome activation in S1P-treated BMMs in vitro and bile duct ligation-induced cholestatic liver injury in vivo [23,24]. In addition to S1P 2 , other receptor subtypes regulate NLRP3 activity.…”

Section: Discussionmentioning

confidence: 82%

“…The current study showed that PI3K and ERK1/2, but not p38 and JNK, mediated the S1P/S1P 2 signaling-dependent NLRP3 upregulation in LPS-primed BMDMs. When compared to a previous study [23], it may be either similar or reversed. In BMMs, ERK1/2 and JNK were involved in NLRP3 upregulation and p38 was involved in pro-IL-1β upregulation, indicating that all three MAPKs influence S1P-induced NLRP3 priming [23].…”

Section: Discussionmentioning

confidence: 88%

See 2 more Smart Citations

S1P/S1P2 Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide

Lee

Choi

2021

Antioxidants

View full text Add to dashboard Cite

The activation of NLRP3 inflammasome is a key factor for various inflammatory diseases. Here, we provide experimental evidence supporting the regulatory role of sphingosine-1-phosphate (S1P) in NLRP3 inflammasome activation in mouse bone-marrow-derived macrophages (BMDMs), along with the S1P receptor subtype involved and underlying regulatory mechanisms. During the priming stage, S1P induced NLRP3 upregulation in BMDMs only when primed with lipopolysaccharide (LPS). In this event, S1P2, but not S1P1, was involved based on the attenuated NLRP3 upregulation with JTE013 (S1P2 antagonist) or S1P2 knockdown. During the activation stage, S1P induced NLRP3 inflammasome activation in LPS-primed BMDMs via caspase-1 activation, interleukin 1β maturation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, and IL-1β secretion. Such NLRP3 inflammasome activation was blocked by either pharmacological inhibition or genetic knockdown of S1P2. NF-κB, PI3K/Akt, and ERK1/2 were identified as effector pathways underlying S1P/S1P2 signaling in the regulation of NLRP3 upregulation in LPS-primed BMDMs. Further, reactive oxygen species (ROS) production was dependent on the S1P/S1P2 signaling axis in these cells, and the ROS generated regulate NLRP3 inflammasome activation, but not NLRP3 priming. Collectively, our findings suggest that S1P promotes NLRP3 upregulation and NLRP3 inflammasome activation in LPS-primed BMDMs via S1P2 and subsequent effector pathways.

show abstract

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 88%

See 1 more Smart Citation

S1P/S1P2 Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide

Lee

Choi

2021

Antioxidants

View full text Add to dashboard Cite

show abstract

“…Recent evidence showed that targeting the S1P/S1PR signaling pathway is crucial for the treatment of immune-mediated diseases (multiple sclerosis and rheumatoid arthritis) [23][24][25], inflammatory bowel diseases [26], lung diseases [27,28], liver diseases [29,30], vascular diseases [31][32][33], brain diseases [34,35], renal diseases [36], and allergy [37]. In the latest clinical trial research, S1P/S1PR also act as a potential new adjuvant therapy to alleviate viral infection of COVID-19 symptoms [38].…”

Section: Introductionmentioning

confidence: 99%

“…For example, in peritoneal macrophages, S1P 1 acts as a pro-migratory signal involving Rho kinase and PI3K-Akt1 [21,47]. Conversely, S1P 2 signaling stimulates cAMP production to inhibit macrophage migration via NLRP3 inflammasome activation, thereby attenuating phosphorylation of Akt in peritoneal inflammation [30,48]. Meanwhile, S1P 3 has been shown to promote activation of inflammatory macrophages in microglia, while a model of brain ischemia has demonstrated that S1P 3 regulates expression levels of inflammatory genes (e.g., IL-6, IL-1β, TNF-α, iNOS, and COX-2) via induction of lipopolysaccharide (LPS) [49,50].…”

Section: Introductionmentioning

confidence: 99%

Macrophage Motility in Wound Healing Is Regulated by HIF-1α via S1P Signaling

Hutami

Izawa

Khurel‐Ochir

et al. 2021

IJMS

View full text Add to dashboard Cite

Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1α is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1α regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1α have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1α/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1α is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing.

show abstract

An overview of sphingosine‐1‐phosphate receptor 2: Structure, biological function, and small‐molecule modulators

Hao,

Luo,

Jiang

et al. 2024

Medicinal Research Reviews

View full text Add to dashboard Cite

Over the past decade, there has been a notable increase in research on sphingosine‐1‐phosphate receptor 2 (S1PR2), which is a type of G‐protein‐coupled receptor. Upon activation by S1P or other ligands, S1PR2 initiates downstream signaling pathways such as phosphoinositide 3‐kinase (PI3K), Mitogen‐activated protein kinase (MAPK), Rho/Rho‐associated coiled‐coil containing kinases (ROCK), and others, contributing to the diverse biological functions of S1PR2 and playing a pivotal role in various physiological processes and disease progressions, such as multiple sclerosis, fibrosis, inflammation, and tumors. Due to the extensive biological functions of S1PR2, many S1PR2 modulators, including agonists and antagonists, have been developed and discovered by pharmaceutical companies (e.g., Novartis and Galapagos NV) and academic medicinal chemists for disease diagnosis and treatment. However, few reviews have been published that comprehensively overview the functions and regulators of S1PR2. Herein, we provide an in‐depth review of the advances in the function of S1PR2 and its modulators. We first summarize the structure and biological function of S1PR2 and its pathological role in human diseases. We then focus on the discovery approach, design strategy, development process, and biomedical application of S1PR2 modulators. Additionally, we outline the major challenges and future directions in this field. Our comprehensive review will aid in the discovery and development of more effective and clinically applicable S1PR2 modulators.

show abstract

NLRP3 inflammasome priming and activation in cholestatic liver injury via the sphingosine 1-phosphate/S1P receptor 2/Gα(12/13)/MAPK signaling pathway

Cited by 34 publications

References 45 publications

S1P/S1P2 Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide

S1P/S1P2 Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide

Macrophage Motility in Wound Healing Is Regulated by HIF-1α via S1P Signaling

An overview of sphingosine‐1‐phosphate receptor 2: Structure, biological function, and small‐molecule modulators

Contact Info

Product

Resources

About