NLRP7 and related inflammasome activating pattern recognition receptors and their function in host defense and disease

Radian, Alexander D.; Almeida, Lúcia de; Dorfleutner, Andrea; Stehlik, Christian

doi:10.1016/j.micinf.2013.04.001

Cited by 39 publications

(37 citation statements)

References 80 publications

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“…2b , right panel). The short isoform (MW ~105 kDa) of NLRP7 increased to a greater extent than the long isoform (MW ~118 kDa) on day 6 after decidualization [ 29 ]. These results show that NLRP7 was up-regulated gradually with in vitro decidualized T-HESCs.…”

Section: Resultsmentioning

confidence: 99%

NLRP7 contributes to in vitro decidualization of endometrial stromal cells

Huang

et al. 2017

Reprod Biol Endocrinol

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BackgroundNucleotide-binding oligomerization domain (NACHT), leucine rich repeat (LRR) and pyrin domain (PYD) 7 containing protein, NLRP7, is a member of the NLR family which serves as innate immune sensors. Mutations and genetic variants of NLRP7 have been found in women with infertility associated conditions, such as recurrent hydatidiform mole, recurrent miscarriage, and preeclampsia. Decidualization of endometrial stromal cells is a hallmark of tissue remodeling to support embryo implantation and proper placental development. Given defective decidualization has been implicated in miscarriage as well as preeclampsia, we aimed to explore the link between the NLRP7 gene and decidualization.MethodsEndometrial samples obtained from pregnant women in the first trimester and non-pregnant women were used to study NLRP7 expression pattern. The human telomerase reverse transcriptase (hTERT)-immortalized human endometrial stromal cells (T-HESCs) were used to study the effect of NLRP7 on decidualization. Decidualization of T-HESCs was induced with 1 μM medroxyprogesterone acetate (MPA) and 0.5 mM 8-bromoadenosine 3':5'-cyclic monophosphate (8-Br-cAMP). siRNA was used to knock down NLRP7 while lentiviral vectors were used to overexpress NLRP7 in cells. NLRP7 expression was detected by immunofluorescence, qRT-PCR, and Western blotting. Decidualization markers, Insulin-like growth factor-binding protein 1 (IGFBP-1) and prolactin (PRL), were detected by qRT-PCR and ELISA. Nuclear translocation of NLRP7 was detected by the subcellular fractionation and confocal microscopy. The effect of NLRP7 on progesterone receptor (PR) activity was evaluated by a reporter system.ResultsNLRP7 was up-regulated in the decidual stromal cells of human first-trimester endometrium. After in vitro decidualization, T-HESCs presented with the swollen phenotype and increased expressions of IGFBP-1 and PRL. Knockdown or over-expression of NLRP7 reduced or enhanced the decidualization, respectively, according to the expression level of IGFBP-1. NLRP7 was found to translocate in the nucleus of decidualized T-HESCs and able to promote PR activity.ConclusionsNLRP7 was upregulated and translocated to the nucleus of the endometrial stromal cells in an in vitro decidualization model. Overexpressed NLRP7 promoted the IGFBP-1 expression and PR reporter activation. IGFBP-1 expression decreased with the knockdown of NLRP7. Therefore, we suggest that NLRP7 contributes to in vitro decidualization of endometrial stromal cells.

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Section: Resultsmentioning

confidence: 99%

NLRP7 contributes to in vitro decidualization of endometrial stromal cells

Huang

et al. 2017

Reprod Biol Endocrinol

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“…NLRP7 belongs to the NLRP subfamily and forms an ASC and caspase-1-containing inflammasome in human macrophages in response to microbial acylated lipopeptides (acLP) and bacterial infection with Staphylococcus aureus and Listeria monocytogenes (Khare et al, 2012; Radian et al, 2013). Accordingly, NLRP7 is present in high molecular weight complexes following S. aureus infection (Khare et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

ATP binding by NLRP7 is required for inflammasome activation in response to bacterial lipopeptides

Radian

Khare

Chu

et al. 2015

Molecular Immunology

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Nucleotide-binding oligimerization domain (NOD)-like receptors (NLRs) are pattern recognition receptors (PRRs) involved in innate immune responses. NLRs encode a central nucleotide-binding domain (NBD) consisting of the NAIP, CIITA, HET-E and TP1 (NACHT) domain and the NACHT associated domain (NAD), which facilitates receptor oligomerization and downstream inflammasome signaling. The NBD contains highly conserved regions, known as Walker motifs, that are required for nucleotide binding and hydrolysis. The NLR containing a PYRIN domain (PYD) 7 (NLRP7) has been recently shown to assemble an ASC and caspase-1-containing high molecular weight inflammasome complex in response to microbial acylated lipopeptides and Staphylococcus aureus infection. However, the molecular mechanism responsible for NLRP7 inflammasome activation is still elusive. Here we demonstrate that the NBD of NLRP7 is an ATP binding domain and has ATPase activity. We further show that an intact nucleotide-binding Walker A motif is required for NBD-mediated nucleotide binding and hydrolysis, oligomerization, and NLRP7 inflammasome formation and activity. Accordingly, THP-1 cells expressing a mutated Walker A motif display defective NLRP7 inflammasome activation, interleukin (IL)-1β release and pyroptosis in response to acylated lipopeptides and S. aureus infection. Taken together, our results provide novel insights into the mechanism of NLRP7 inflammasome assembly.

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“…NLRP7 expression is induced in response to LPS and IL-1β in peripheral blood mononuclear cells (PBMC) and is detected at high levels in thymus, spleen and bone marrow, suggesting a role in host defence. NLRP3 mediated inflammasome assembly has been demonstrated to be important in both human and mouse models of IBD 23 and similarly it is known that the NLRP7 protein can promote both positive and negative regulation of inflammasome activity 24 . For example, it is required for bacterial acylated lipoprotein-mediated Caspase-1 activation and maturation of IL-1β and IL-18, but has also been shown to inhibit NLRP3 and Caspase-1-mediated IL-1β release.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing and genotyping identify a rare variant inNLRP7gene associated with ulcerative colitis

Onoufriadis

Stone

Katsiamides

et al. 2017

Preprint

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Background and aimsAlthough genome-wide association studies (GWAS) in inflammatory bowel disease (IBD) have identified a large number of common disease susceptibility alleles for both Crohn’s disease (CD) and ulcerative colitis (UC), a substantial fraction of IBD heritability remains unexplained, suggesting that rare coding genetic variants may also have a role in pathogenesis. We used high-throughput sequencing in families with multiple cases of IBD, followed by genotyping of cases and controls, to investigate whether rare protein altering genetic variants are associated with susceptibility to IBD.MethodsWhole exome sequencing was carried out in 10 families in which 3 or more individuals were affected with IBD. A stepwise filtering approach was applied to exome variants to identify potential causal variants. Follow-up genotyping was performed in 6,025 IBD cases (2,948 CD; 3,077 UC) and 7,238 controls.ResultsOur exome variant analysis revealed coding variants in the NLRP7 gene that were present in affected individuals in two distinct families. Genotyping of the two variants, p.S361L and p.R801H, in IBD cases and controls showed that the p.S361L variant was significantly associated with an increased risk of ulcerative colitis (odds ratio 4.79, p=0.0039) and IBD (odds ratio 3.17, p=0.037). A combined analysis of both variants showed suggestive association with an increased risk of IBD (odds ratio 2.77, p=0.018).ConclusionsThe results suggest that NLRP7 signalling and inflammasome formation may be a significant component in the pathogenesis of IBD.

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NLRP7 and related inflammasome activating pattern recognition receptors and their function in host defense and disease

Cited by 39 publications

References 80 publications

NLRP7 contributes to in vitro decidualization of endometrial stromal cells

NLRP7 contributes to in vitro decidualization of endometrial stromal cells

ATP binding by NLRP7 is required for inflammasome activation in response to bacterial lipopeptides

Exome sequencing and genotyping identify a rare variant inNLRP7gene associated with ulcerative colitis

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