VSIG4 mediates transcriptional inhibition of
            <i>Nlrp3</i>
            and
            <i>Il-1</i>
            β in macrophages

Huang, Xiaoyong; Feng, Zeqing; Jiang, Yuanzhong; Li, Jialin; Xiang, Qun; Guo, Sheng; Yang, Chengying; Lei, Fei; Guo, Guoning; Zheng, Lixin; Wu, Yuzhang; Chen, Yongwen

doi:10.1126/sciadv.aau7426

Cited by 83 publications

(64 citation statements)

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“…In light of the data, we contemplate that interruption of IL-1β/IL-1R1 signaling is responsible for elaboration of DSS-mediated colitis, although aware of the fact that using IL-1Rα would also interrupt IL-1α/IL-1R interactions. In considering with our recent work showing that the resistance of Vsig4 −/− mice to DSS-mediated colitis is dependent on the dysregulation of NLRP3/Caspase-1/IL-1β/IL-18 axis ( 13 ), we postulate that hyperactivation of the NLRP3 inflammasome in gut macrophages can exert a protective effect on acute colitis.…”

Section: Discussionsupporting

confidence: 72%

“…Dysregulation of the NLRP3 inflammasome has been shown to affect the pathogenesis of DSS-induced acute colitis ( 12 , 13 ). Therefore, we investigated the functions of CD1d1 in the activation of DSS-induced NLRP3 inflammasome.…”

Section: Resultsmentioning

confidence: 99%

“…To further explore the immediate signaling events of iGB3/CD1d1 that lead to NF-κB inactivation, we applied a yeast split-ubiquitin screening system ( 13 ) using a mouse CD1d1 C-terminal ubiquitin fusion (pBT3-SUC- CD1d1 ) as the bait against a complementary DNA (cDNA) library constructed from mouse BMDMs (fig. S6A), and we identified 10 candidate CD1d1-interactive genes among 1419 selected clones (fig.…”

Section: Resultsmentioning

confidence: 99%

“…The roles of NLRP3 inflammasome in the pathogenesis of DSS-caused colitis have also been extensively studied, with the results showing that loss of epithelial integrity and massive leukocyte infiltration appear to associate with Nlrp3 −/− and Casp-1 −/− mice for developing more severe colitis ( 12 ). Our recent work has also demonstrated that dysregulation of NLRP3 inflammasome activity in Vsig4 −/− [V-set and immunoglobulin (Ig) domain-containing 4] in mice renders protection to DSS-mediated colitis ( 13 ). However, factors that induce NLRP3 inflammasome hyperactivation within colonic tissues in response to DSS are still unclear.…”

Section: Introductionmentioning

confidence: 99%

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CD1d1 intrinsic signaling in macrophages controls NLRP3 inflammasome expression during inflammation

Cui

Wang

et al. 2020

Sci. Adv.

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Dysregulation of immune responses in the gut often associates with inflammatory bowel diseases (IBD). Mouse CD1d1, an ortholog of human CD1d mainly participating in lipid-antigen presentation to NKT cells, is able to generate intrinsic signals upon stimulation. Mice with macrophage-specific CD1d1 deficiency (LymCD1d1−/−) acquire resistance to dextran sodium sulfate (DSS)–induced colitis, attributing to the transcriptional inhibition of NLRP3 inflammasome components. The hyperactivation of NLRP3 inflammasome accounts for gut epithelial proliferation and intestine-blood barrier integrity. Mechanistically, occupancy by the natural ligand glycosphingolipid iGb3, CD1d1 responds with intracellular Ser330 dephosphorylation thus to reduce the Peroxiredoxin 1 (PRDX1)–associated AKT-STAT1 phosphorylation and subsequent NF-κB activation, eventually causing transcriptional down-regulation of Nlrp3 and its immediate substrates Il1b and Il18 in macrophages. Therefore, the counterbalancing role of CD1d1 in macrophages appears to determine severity of DSS-mediated colitis in mice. These findings propose new intervention strategies for treating IBD and other inflammatory disorders.

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Section: Discussionsupporting

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CD1d1 intrinsic signaling in macrophages controls NLRP3 inflammasome expression during inflammation

Cui

Wang

et al. 2020

Sci. Adv.

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“…In addition, other studies have shown that the NLRP3 NACHT domain molecule may be the target for drug development against cardiovascular diseases. Blocking ATP 5 Oxidative Medicine and Cellular Longevity hydrolysis could inhibit NLRP3 activation and inflammasome formation [62,63].…”

Section: Discussionmentioning

confidence: 99%

NLRP3 Inflammasome and Its Central Role in the Cardiovascular Diseases

Tong

Wang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background/Aims. NLRP3 inflammasome, an inflammasome which consists of nucleotide-binding oligomerization domain- (Nod-) like receptor3 (NLRP3) scaffold, apoptosis-associated speck-like protein (ASC) containing a CARD adaptor, and pro-caspase-1, is assembled after the cytoplasmic leucine-rich repeats (LRRs) of NLRP3 sense pathogens or danger signals. In recent years, the role of inflammasome in cardiovascular diseases has attracted mounting attention, and the in-depth study of its mechanism is gradually clear. Materials. The NLRP3 inflammasome controls the activation of the proteolytic enzyme caspase-1. Caspase-1 in turn regulates the maturation of the proinflammasome cytokines IL-1β and IL-18, which leads to an inflammatory response. We made a mini-review on the association of regulatory mechanisms of NLRP3 inflammasome with the development of cardiovascular diseases systematically based on the recent research studies. Discussion. The inflammasome plays an indispensable role in the development of atherosclerosis, coronary heart diseases (CHD), and heart ischemia-reperfusion (I/R) injury, and NLRP3 inflammasome may become a new target for the prevention and treatment of cardiovascular diseases. Effective regulation of NLRP3 may help prevent or even treat cardiovascular diseases. Conclusion. This mini-review focuses on the association of regulatory mechanisms of NLRP3 inflammasome with the development of cardiovascular diseases, which may supply some important clues for future therapies and novel drug targets for cardiovascular diseases.

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V‐Set Immunoglobulin Domain–Containing Protein 4 as a Novel Serum Biomarker of Lupus Nephritis and Renal Pathology Activity

Tang,

Zhang,

Teymur

et al. 2023

Arthritis & Rheumatology

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ObjectiveTo discover novel serum biomarkers that have diagnostic or predictive value in lupus nephritis (LN).MethodsUsing a quantitative protein microarray, we screened for high‐abundant proteome expression in the serum of patients with LN compared to healthy controls. Top candidates from this screening were validated using a larger cohort of patients with LN compared to a disease control cohort (subjects with other chronic kidney diseases) and a healthy control cohort. Promising markers were then selected using a machine‐learning model and further validated with a larger patient cohort. The corresponding autoantibodies and immune complexes containing these proteins were also examined.ResultsIn total, 13 proteins were found to be significantly elevated in LN patient serum in the screening, among which 8 proteins were validated by enzyme‐linked immunosorbent assay using 81 serum samples from LN patients and control subjects. Three serum markers with LN diagnostic potential were identified using feature importance analysis and further validated using 155 serum samples from LN patients and control subjects. V‐set immunoglobulin domain–containing protein 4 (VSIG4) appeared to be the most promising marker in distinguishing LN from healthy controls, with an area under the curve of 0.93. VSIG4 could also discriminate active LN from inactive LN. Furthermore, serum VSIG4 levels were positively correlated with all of the following clinical parameters: the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (Spearman's rank correlation rs = 0.42, P < 0.001), the renal domain score of the SLEDAI (rs = 0.46, P < 0.001), the urinary protein‐to‐creatinine ratio (rs = 0.56, P < 0.001), and the serum creatinine level (rs = 0.41, P < 0.001). Importantly, we found that serum VSIG4 levels tracked with LN disease activity longitudinally, and that serum VSIG4 levels reflected the renal pathology activity index (AI), particularly the AI components of crescent formation and hyaline deposits.ConclusionVSIG4 may be a promising novel serum biomarker and therapeutic target in patients with LN.image

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VSIG4 mediates transcriptional inhibition of Nlrp3 and Il-1 β in macrophages

Abstract: VSIG4 controls inflammation through MS4A6D-mediated transcriptional inhibition of Nlrp3 and Il-1β in macrophages.

Cited by 83 publications

References 40 publications

CD1d1 intrinsic signaling in macrophages controls NLRP3 inflammasome expression during inflammation

CD1d1 intrinsic signaling in macrophages controls NLRP3 inflammasome expression during inflammation

NLRP3 Inflammasome and Its Central Role in the Cardiovascular Diseases

V‐Set Immunoglobulin Domain–Containing Protein 4 as a Novel Serum Biomarker of Lupus Nephritis and Renal Pathology Activity

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