S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β

Metastasis is the primary cause of cancer death. The inflammatory tumor microenvironment contributes to metastasis, for instance, by recruiting blood and lymph vessels. Among tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) take a center stage in promoting both tumor angiogenesis and metastatic spread. We found that genetic deletion of the S1P receptor 1 (S1pr1) alone in CD11bhi CD206+ TAMs infiltrating mouse breast tumors prevents pulmonary metastasis and tumor lymphangiogenesis. Reduced lymphangiogenesis was also observed in the nonrelated methylcholanthrene-induced fibrosarcoma model. Transcriptome analysis of isolated TAMs from both entities revealed reduced expression of the inflammasome component Nlrp3 in S1PR1-deficient TAMs. Macrophage-dependent lymphangiogenesis in vitro was triggered upon inflammasome activation and required both S1PR1 signaling and IL-1β production. Finally, NLRP3 expression in tumor-infiltrating macrophages correlated with survival, lymph node invasion, and metastasis of mammary carcinoma patients. Conceptually, our study indicates an unappreciated role of the NLRP3 inflammasome in promoting metastasis via the lymphatics downstream of S1PR1 signaling in macrophages.

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New mutant mouse models clarify the role of NAIPs, phosphorylation, NLRP3, and tumors in NLRC4 inflammasome activation

10.1101/765313 ◽

2019 ◽

Cited By ~ 1

Author(s):

Jeannette L. Tenthorey ◽

Roberto A. Chavez ◽

Thornton W. Thompson ◽

Katherine A. Deets ◽

Russell E. Vance ◽

...

Keyword(s):

Immune Responses ◽

Mutant Mouse ◽

Adaptor Protein ◽

Underlying Mechanism ◽

Inflammasome Activation ◽

Biological Functions ◽

Inflammasome Component

ABSTRACTThe NAIP/NLRC4 inflammasome is a cytosolic sensor of bacteria that activates Caspase-1 and initiates potent downstream immune responses. Structural, biochemical, and genetic data all demonstrate that the NAIP proteins act as receptors for specific bacterial ligands, while NLRC4 is a downstream adaptor protein that multimerizes with NAIPs to form a macromolecular structure called an inflammasome. However, several aspects of NLRC4 biology remain unresolved. For example, in addition to its clear function in responding to bacteria, NLRC4 has also been proposed to initiate anti-tumor responses, though the underlying mechanism is unknown. NLRC4 has also been shown to be phosphorylated on serine 533, and this modification was suggested to be important for NLRC4 function. In the absence of S533 phosphorylation, it was further proposed that another inflammasome component, NLRP3, can induce NLRC4 activation. We generated a new Nlrc4-deficient mouse line as well as mice encoding phosphomimetic S533D and non-phosphorylatable S533A NLRC4 proteins. Using these genetic models in vivo and in vitro, we fail to observe a role for phosphorylation in NLRC4 inflammasome function. Furthermore, we find no role for NLRP3 in NLRC4 function, or for NLRC4 in a model of melanoma. These results simplify and clarify our understanding of the mechanism of NAIP/NLRC4 activation and its biological functions.

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miR-29a-5p Alleviates Traumatic Brain Injury (TBI)-Induced Permeability Disruption Via Regulating NLRP3 Pathway

10.21203/rs.3.rs-334899/v1 ◽

2021 ◽

Author(s):

Aijun Zhang ◽

Youming Lu ◽

Lei Yuan ◽

Pengqi Zhang ◽

Dongdong Zou ◽

...

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Endothelial Cell ◽

Brain Injury ◽

Inflammasome Activation ◽

Caspase 1 ◽

Promising Strategy ◽

Pathway Activation ◽

Nlrp3 Expression

Abstract Blood-brain barrier (BBB) dysfunction is presented during traumatic brain injury (TBI) and is dependent upon the activation of the NLRP3/Caspase-1 inflammasome pathway. MicroRNA (miRNA) was proved to inhibit signaling pathway activation by targeting gene expression and we predicated in the database that miR-29a targets to NLRP3. Herein, this study aims to define the regulating role of miR-29a in NLRP3 expression and NLRP3/Caspase-1 inflammasome activation in TBI-induced BBB dysfunction. Our results indicated that miR-29a-5p alleviates TBI-induced the increased permeability of endothelial cell and BBB via suppressing NLRP3 expression and NLRP3/Caspase-1 inflammasome activation, providing a promising strategy for relieving TBI via inhibiting NLRP3/Caspase-1 inflammasome activation.

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Macrophage Uptake of Necrotic Cell DNA Activates the AIM2 Inflammasome to Regulate a Proinflammatory Phenotype in CKD

Journal of the American Society of Nephrology ◽

10.1681/asn.2017080863 ◽

2018 ◽

Vol 29 (4) ◽

pp. 1165-1181 ◽

Cited By ~ 32

Author(s):

Takanori Komada ◽

Hyunjae Chung ◽

Arthur Lau ◽

Jaye M. Platnich ◽

Paul L. Beck ◽

...

Keyword(s):

Bone Marrow ◽

Inflammasome Activation ◽

Dna Uptake ◽

Chronic Injury ◽

Caspase 1 ◽

Double Stranded Dna ◽

Molecular Pattern ◽

Macrophage Uptake

Nonmicrobial inflammation contributes to CKD progression and fibrosis. Absent in melanoma 2 (AIM2) is an inflammasome-forming receptor for double-stranded DNA. AIM2 is expressed in the kidney and activated mainly by macrophages. We investigated the potential pathogenic role of the AIM2 inflammasome in kidney disease. In kidneys from patients with diabetic or nondiabetic CKD, immunofluorescence showed AIM2 expression in glomeruli, tubules, and infiltrating leukocytes. In a mouse model of unilateral ureteral obstruction (UUO), Aim2 deficiency attenuated the renal injury, fibrosis, and inflammation observed in wild-type (WT) littermates. In bone marrow chimera studies, UUO induced substantially more tubular injury and IL-1β cleavage in Aim2−/− or WT mice that received WT bone marrow than in WT mice that received Aim2−/− bone marrow. Intravital microscopy of the kidney in LysM(gfp/gfp) mice 5–6 days after UUO demonstrated the significant recruitment of GFP+ proinflammatory macrophages that crawled along injured tubules, engulfed DNA from necrotic cells, and expressed active caspase-1. DNA uptake occurred in large vacuolar structures within recruited macrophages but not resident CX3CR1+ renal phagocytes. In vitro, macrophages that engulfed necrotic debris showed AIM2-dependent activation of caspase-1 and IL-1β, as well as the formation of AIM2+ ASC specks. ASC specks are a hallmark of inflammasome activation. Cotreatment with DNaseI attenuated the increase in IL-1β levels, confirming that DNA was the principal damage-associated molecular pattern in this process. Therefore, the activation of the AIM2 inflammasome by DNA from necrotic cells drives a proinflammatory phenotype that contributes to chronic injury in the kidney.

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The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing M1 macrophage polarization in mice

Blood ◽

10.1182/blood.2019003990 ◽

2020 ◽

Vol 136 (4) ◽

pp. 501-515 ◽

Cited By ~ 8

Author(s):

Kunpeng Wu ◽

Yan Yuan ◽

Huihui Yu ◽

Xin Dai ◽

Shu Wang ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Macrophage Polarization ◽

Short Chain Fatty Acids ◽

Inflammasome Activation ◽

Microbial Metabolites ◽

M1 Macrophage ◽

The Impact

Abstract The diversity of the human microbiome heralds the difference of the impact that gut microbial metabolites exert on allogenic graft-versus-host (GVH) disease (GVHD), even though short-chain fatty acids and indole were demonstrated to reduce its severity. In this study, we dissected the role of choline-metabolized trimethylamine N-oxide (TMAO) in the GVHD process. Either TMAO or a high-choline diet enhanced the allogenic GVH reaction, whereas the analog of choline, 3,3-dimethyl-1-butanol reversed TMAO-induced GVHD severity. Interestingly, TMAO-induced alloreactive T-cell proliferation and differentiation into T-helper (Th) subtypes was seen in GVHD mice but not in in vitro cultures. We thus investigated the role of macrophage polarization, which was absent from the in vitro culture system. F4/80+CD11b+CD16/32+ M1 macrophage and signature genes, IL-1β, IL-6, TNF-α, CXCL9, and CXCL10, were increased in TMAO-induced GVHD tissues and in TMAO-cultured bone marrow–derived macrophages (BMDMs). Inhibition of the NLRP3 inflammasome reversed TMAO-stimulated M1 features, indicating that NLRP3 is the key proteolytic activator involved in the macrophage’s response to TMAO stimulation. Consistently, mitochondrial reactive oxygen species and enhanced NF-κB nuclear relocalization were investigated in TMAO-stimulated BMDMs. In vivo depletion of NLRP3 in GVHD recipients not only blocked M1 polarization but also reversed GVHD severity in the presence of TMAO treatment. In conclusion, our data revealed that TMAO-induced GVHD progression resulted from Th1 and Th17 differentiation, which is mediated by the polarized M1 macrophage requiring NLRP3 inflammasome activation. It provides the link among the host choline diet, microbial metabolites, and GVH reaction, shedding light on alleviating GVHD by controlling choline intake.

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IL1RAP potentiates multiple oncogenic signaling pathways in AML

Journal of Experimental Medicine ◽

10.1084/jem.20180147 ◽

2018 ◽

Vol 215 (6) ◽

pp. 1709-1727 ◽

Cited By ~ 18

Author(s):

Kelly Mitchell ◽

Laura Barreyro ◽

Tihomira I. Todorova ◽

Samuel J. Taylor ◽

Iléana Antony-Debré ◽

...

Keyword(s):

Tyrosine Kinases ◽

Interleukin 1 ◽

Oncogenic Signaling ◽

Genetic Deletion ◽

Mechanistic Basis ◽

Oncogenic Signaling Pathways ◽

Receptor Accessory Protein

The surface molecule interleukin-1 receptor accessory protein (IL1RAP) is consistently overexpressed across multiple genetic subtypes of acute myeloid leukemia (AML) and other myeloid malignancies, including at the stem cell level, and is emerging as a novel therapeutic target. However, the cell-intrinsic functions of IL1RAP in AML cells are largely unknown. Here, we show that targeting of IL1RAP via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo, without perturbing healthy hematopoietic function or viability. Furthermore, we found that the role of IL1RAP is not restricted to the IL-1 receptor pathway, but that IL1RAP physically interacts with and mediates signaling and pro-proliferative effects through FLT3 and c-KIT, two receptor tyrosine kinases with known key roles in AML pathogenesis. Our study provides a new mechanistic basis for the efficacy of IL1RAP targeting in AML and reveals a novel role for this protein in the pathogenesis of the disease.

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Upregulation of OSBPL3 by HIF1A promotes colorectal cancer progression through activation of RAS signaling pathway

Cell Death and Disease ◽

10.1038/s41419-020-02793-3 ◽

2020 ◽

Vol 11 (7) ◽

Cited By ~ 1

Author(s):

Hong-li Jiao ◽

Bin-shu Weng ◽

Shan-shan Yan ◽

Zi-mo Lin ◽

Shu-yang Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Signaling Pathway ◽

Cancer Progression ◽

Ras Signaling ◽

Invasion And Metastasis ◽

In Vivo Models ◽

Ras Signaling Pathway ◽

Colorectal Cancer Progression

AbstractOxysterol-binding protein like protein 3 (OSBPL3) has been shown involving in the development of several human cancers. However, the relationship between OSBPL3 and colorectal cancer (CRC), particularly the role of OSBPL3 in the proliferation, invasion and metastasis of CRC remains unclear. In this study, we investigated the role of OSBPL3 in CRC and found that its expression was significantly higher in CRC tissues than that in normal tissues. In addition, high expression of OSBPL3 was closely related to poor differentiation, advanced TNM stage and poor prognosis of CRC. Further experiments showed that over-expression of OSBPL3 promoted the proliferation, invasion and metastasis of CRC in vitro and in vivo models. Moreover, we revealed that OSBPL3 promoted CRC progression through activation of RAS signaling pathway. Furthermore, we demonstrated that hypoxia induced factor 1 (HIF-1A) can regulate the expression of OSBPL3 via binding to the hypoxia response element (HRE) in the promoter of OSBPL3. In summary, Upregulation of OSBPL3 by HIF1A promotes colorectal cancer progression through activation of RAS signaling pathway. This novel mechanism provides a comprehensive understanding of both OSBPL3 and the RAS signaling pathway in the progression of CRC and indicates that the HIF1A–OSBPL3–RAS axis is a potential target for early therapeutic intervention in CRC progression.

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RhTrx-1 ameliorates miroglial neuroinflammation after cerebral ischemic stroke

10.21203/rs.3.rs-18172/v1 ◽

2020 ◽

Author(s):

Yang Jiao ◽

Jianjian Wang ◽

Huixue Zhang ◽

Yuze Cao ◽

Yang Qu ◽

...

Keyword(s):

Ischemic Stroke ◽

Inflammatory Response ◽

Inflammatory Responses ◽

Inflammatory Factors ◽

Experimental Stroke ◽

Inflammasome Activation ◽

Cerebral Ischemic

Abstract Background Microglia are rapidly activated after ischemic stroke and participate in the occurrence of neuroinflammation, which exacerbates the injury of ischemic stroke. Receptor Interacting Serine Threonine Kinase 1 (RIPK1) is thought to be involved in the development of inflammatory responses, but its role in ischemic microglia remains unclear. Here, we applied recombinant human thioredoxin-1 (rhTrx-1), a potential neuroprotective agent, to explore the role of rhTrx-1 in inhibiting RIPK1-mediated neuroinflammatory responses in microglia. Method Middle cerebral artery occlusion (MCAO) and Oxygen and glucose deprivation (OGD) were conducted for in vivo and in vitro experimental stroke models. The expression of RIPK1 in microglia after ischemia was examined. The inflammatory response of microglia was analyzed after treatment with rhTrx-1 and Necrostatin-1 (Nec-1, inhibitors of RIPK1), and the mechanisms were explored. In addition, the effects of rhTrx-1 on neurobehavioral deficits and cerebral infarct volume were examined. Results RIPK1 expression was detected in microglia after ischemia. Molecular docking results showed that rhTrx-1 could directly bind to RIPK1. In vitro experiments found that rhTrx-1 reduced necroptosis, mitochondrial membrane potential damage, Reactive oxygen species (ROS) accumulation and NLR Family, pyrin domain-containing 3 protein (NLRP3) inflammasome activation by inhibiting RIPK-1 expression, and regulated microglial M1/M2 phenotypic changes, thereby reducing the release of inflammatory factors. Consistently, in vivo experiments found that rhTrx-1 treatment attenuated cerebral ischemic injury by inhibiting the inflammatory response. Conclusion Our study demonstrates the role of RIPK1 in microglia-arranged neuroinflammation after cerebral ischemia. Administration of rhTrx-1 provides neuroprotection in ischemic stroke-induced microglial neuroinflammation by inhibiting RIPK1 expression.

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Inhibitory Role of Berberine, an Isoquinoline Alkaloid, on NLRP3 Inflammasome Activation for the Treatment of Inflammatory Diseases

Molecules ◽

10.3390/molecules26206238 ◽

2021 ◽

Vol 26 (20) ◽

pp. 6238

Author(s):

Paromita Sarbadhikary ◽

Blassan P. George ◽

Heidi Abrahamse

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammatory Diseases ◽

In Vivo Studies ◽

Inflammasome Activation ◽

Inflammatory Disorders ◽

Nlrp3 Inflammasome Activation ◽

Anti Inflammatory

The pyrin domain-containing multiprotein complex NLRP3 inflammasome, consisting of the NLRP3 protein, ASC adaptor, and procaspase-1, plays a vital role in the pathophysiology of several inflammatory disorders, including neurological and metabolic disorders, chronic inflammatory diseases, and cancer. Several phytochemicals act as promising anti-inflammatory agents and are usually regarded to have potential applications as complementary or alternative therapeutic agents against chronic inflammatory disorders. Various in vitro and in vivo studies have reported the anti-inflammatory role of berberine (BRB), an organic heteropentacyclic phytochemical and natural isoquinoline, in inhibiting NLRP3 inflammasome-dependent inflammation against many disorders. This review summarizes the mechanism and regulation of NLRP3 inflammasome activation and its involvement in inflammatory diseases, and discusses the current scientific evidence on the repressive role of BRB on NLRP3 inflammasome pathways along with the possible mechanism(s) and their potential in counteracting various inflammatory diseases.

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The role of IL-1 in gout: from bench to bedside

Rheumatology ◽

10.1093/rheumatology/kex449 ◽

2017 ◽

Vol 57 (suppl_1) ◽

pp. i12-i19 ◽

Cited By ~ 10

Author(s):

Alexander So ◽

Alexandre Dumusc ◽

Sonia Nasi

Keyword(s):

Animal Studies ◽

Reactive Oxygen Species Generation ◽

Inflammasome Activation ◽

Acute Gout ◽

Oxygen Species ◽

Biological Responses ◽

Novel Approach ◽

The Subject

Abstract The translation of our knowledge of the biology of MSU crystal-induced IL-1 secretion gives rise to new targets and therapeutic strategies in the treatment of acute gout. The NACHT, LRR and PYD domains-containing protein 3 inflammasome is key to this, and is the subject of intense research. Novel pathways that modulate inflammasome activation, reactive oxygen species generation and extracellular processing of IL-1 have been described and show promise in in vitro and animal studies. Meanwhile, blocking IL-1 by various IL-1 inhibitors has shown the validity of this concept. Patients with acute gout treated with these inhibitors showed positive clinical and biological responses. More work needs to be performed to assess the risk/benefit profile of anti-IL-1 therapies as well as to identify those who will benefit the most from this novel approach to the treatment of gout.

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TRIM28 SUMOylates and stabilizes NLRP3 to facilitate inflammasome activation

Nature Communications ◽

10.1038/s41467-021-25033-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ying Qin ◽

Qi Li ◽

Wenbo Liang ◽

Rongzhen Yan ◽

Li Tong ◽

...

Keyword(s):

Posttranslational Modifications ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Sumo Modification ◽

Nlrp3 Inflammasome Activation ◽

Sumo Ligase ◽

Tripartite Motif ◽

Nlrp3 Expression

AbstractThe cellular NLRP3 protein level is crucial for assembly and activation of the NLRP3 inflammasome. Various posttranslational modifications (PTMs), including phosphorylation and ubiquitination, control NLRP3 protein degradation and inflammasome activation; however, the function of small ubiquitin-like modifier (SUMO) modification (called SUMOylation) in controlling NLRP3 stability and subsequent inflammasome activation is unclear. Here, we show that the E3 SUMO ligase tripartite motif-containing protein 28 (TRIM28) is an enhancer of NLRP3 inflammasome activation by facilitating NLRP3 expression. TRIM28 binds NLRP3, promotes SUMO1, SUMO2 and SUMO3 modification of NLRP3, and thereby inhibits NLRP3 ubiquitination and proteasomal degradation. Concordantly, Trim28 deficiency attenuates NLRP3 inflammasome activation both in vitro and in vivo. These data identify a mechanism by which SUMOylation controls the cellular NLRP3 level and inflammasome activation, and reveal correlations and interactions of NLRP3 SUMOylation and ubiquitination during inflammasome activation.

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