NLR Nod1 signaling promotes survival of BCR-engaged mature B cells through upregulated Nod1 as a positive outcome
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE101318 | GEO | 2017/09/03
SECONDARY ACCESSION(S): PRJNA393997
REPOSITORIES: GEO
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Project description:Although B cell development requires expression of the B cell antigen receptor (BCR), it remains unclear whether engagement of self-antigen provides a positive impact for most B cells. Here, we show that BCR engagement by self-ligand during development in vivo results in up-regulation of the Nod-like receptor member Nod1, which recognizes the products of intestinal commensal bacteria. In anti-thymocyte/Thy-1 autoreactive BCR knock-in mice lacking self-Thy-1 ligand, immunoglobulin light chain editing occurred, generating B cells with up-regulated Nod1, including follicular and marginal zone B cells with natural autoreactivity. This BCR editing with increased Nod1 resulted in preferential survival. In normal adult mice, most mature B cells are enriched for Nod1 up-regulated cells, and signaling through Nod1 promotes competitive survival of mature B cells. These findings demonstrate a role for microbial products in promoting survival of mature B cells through up-regulated Nod1, providing a positive effect of BCR engagement on development of most B cells.
| S-EPMC5626402 | biostudies-literature
Project description:NLR Nod1 signaling promotes survival of BCR-engaged mature B cells through upregulated Nod1 as a positive outcome
| PRJNA393997 | ENA
Project description:Aberrant differentiation of progenitor cells in the hematopoietic system is known to severely impact host immune responsiveness. Here we demonstrate that NOD1, a cytosolic innate sensor of bacterial peptidoglycan, also functions in murine hematopoietic cells as a major regulator of both the generation and differentiation of lymphoid progenitors as well as peripheral T lymphocyte homeostasis. We further show that NOD1 mediates these functions by facilitating STAT5 signaling downstream of hematopoietic cytokines. In steady-state, loss of NOD1 resulted in a modest but significant decrease in numbers of mature T, B and NK cells. During systemic protozoan infection, this defect was markedly enhanced leading to host mortality. Lack of functional NOD1 also impaired T-cell-dependent anti-tumor immunity while preventing colitis. These findings reveal that in addition to its classical role as a bacterial ligand receptor, NOD1 plays an important function in regulating adaptive immunity through interaction with a major host cytokine signaling pathway.
2023-10-25 | GSE236485 | GEO
Project description:Transcriptional profiling of zebrafish embryos comparing control group microinjected with empty plasmid with NOD1 group microinjected with ptGFP1-NOD1 plasmid.
2018-06-22 | GSE116109 | GEO
Project description:Zebrafish embryos microinjected with ptGFP1 (control group) or ptGFP1-NOD1 (NOD1 group)
| PRJNA477292 | ENA
Project description:Chronic inflammation is associated with disruption of cellular homeostasis, yet the underlying mechanisms remain elusive1. Nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2) are intracellular pathogen recognition receptors that activate innate immune responses via sensing bacterial peptidoglycans2-4. We demonstrate that NOD1/2 sense not only microbe-specific molecular patterns but also perturbation of cell homeostasis, and thereby cause inflammation. Host generation of sphingosine-1-phosphate (S1P) via the hydrolysis pathway is essential for NOD1/2 signaling upon such stress. Cytosolic delivery of S1P activates NOD1/2 dependent NF-κB activation and inflammation. Finally, we demonstrate that S1P directly binds to and activates NOD1/2. In sum, we describe a hitherto unknown role of NOD1/2 by revealing that they initiate innate immune responses by surveillance of cellular homeostasis through sensing of cytosolic S1P. Our findings provide a novel link between host cytosolic S1P and NOD1/2 mediated immune activation upon perturbation of cellular homeostasis and thus form the basis for future intervention strategies targeting the S1P-NOD1/2 axis.
2020-01-01 | GSE124828 | GEO
Project description:We previously demonstrated that an innate immune receptor, the nucleotide-binding oligomerization domain-1 (Nod1), was involved in the vascular disease in young and adult mice. However, little is known about the role of Nod1 signaling in fetuses. We administered FK565, one of the Nod1 ligands, to pregnant C57BL/6 mice and examined its effect in the fetuses. Nod1 stimulation increased levels of cytokines in the pregnant mice, placentae and fetuses. We found that FK565 which was administered to the pregnant mice transferred to the fetuses through the placentae, and exerted its effects on fetuses in vivo. Nod1 was abundantly expressed in the arteries, and the vascular tissues predominantly produced CCL2 and IL-6 in response to FK565 compared with other fetal tissues. FK565 induced up-regulation of genes associated with immune response, inflammation and apoptosis in fetal vascular tissues.
2016-01-31 | GSE65188 | GEO
Project description:Inflammation is normally a protective response to defend and restore homeostasis; nonresolving inflammation is a major driver of immune disorders. N6-methyladenosine (m6A) is a prevalent mRNA modification that plays a crucial function in multiple biological processes. The effect of m6A on the immune response has recently been reported. However, the effect is unclear, and the results are contradictory. In this study, the expression of total m6A and the methyltransferase METTL3 decreased in LPS-stimulated macrophages. METTL3 knockdown significantly upregulated expression of proinflammatory cytokines, including TNF-α, IL-6 and NO. RNA sequencing analysis showed that the upregulated genes were enriched in inflammation-related signaling pathways and that the NOD-like receptor signaling pathway might be the target molecules of METTL3. METTL3 depletion resulted in upregulation of the NOD1 pathway without impacting NOD2. Moreover, the increase in proinflammatory cytokines induced by METTL3 knockdown was reversed by blocking the NOD1 pathway using the NOD-IN-1 and ML130 specific inhibitors. Mechanistically, METTL3 knockdown promoted the mRNA expression and stability of NOD1 and RIPK2, and the same results were detected in m6A-binding protein YTHDF1- or YTHDF2-silenced cells. All findings suggested that METTL3 depletion inhibits the degradation of NOD1 and RIPK2 mRNA mediated by YTHDF1 and YTHDF2, which upregulate the NOD1 pathway and subsequently promote the LPS-induced inflammatory response in macrophages.
2022-06-01 | GSE189412 | GEO
Project description:The possibility of specifying functional hematopoietic stem and progenitor cells (HSPCs) from human pluripotent stem cells (hPSCs) would overcome current limitations related to HSPC transplantation. However, generating hPSC-derived HSPCs has been elusive, necessitating a better understanding of the native developmental mechanisms that trigger HSPC specification. Here, we revealed in vivo an intrinsic inflammatory mechanism triggered by Nod1 that drives early hemogenic endothelium (HE) patterning to specify HSPCs. Our genetic and chemical experiments showed that HSPCs failed to specify in the absence of Nod1 and its downstream kinase Ripk2. Rescue experiments demonstrated that Nod1 and Ripk2 acted through NF-kB, and that small Rho GTPases are at the apex of this mechanism. Manipulation of NOD1 in a human system of hPSCs differentiation towards the definitive hematopoietic lineage indicated functional conservation. This work establishes the RAC1-NOD1-RIPK2-NFkB axis as the earliest inflammatory inductor that intrinsically primes the HE for proper HSPC specification. Manipulation of this pathway could help derive a competent HE amenable to specify functional patient specific HSPCs for the treatment of blood disorders. Keywords: NOD1, RIPK2, NF-kB, RAC1, Rho GTPases, Hematopoietic Stem and Progenitor Cell Specification, Hemogenic Endothelium.
2023-10-26 | GSE224708 | GEO
Project description:Altered protein dosage by defects in single genes leads to haploinsufficiencies and monogenic disorders, but the impact of small changes in gene expression on multifactorial disease is unknown. Here we show that a persistent small increase in expression of NOD1, a key innate sensor of bacterial infection, precipitates a large physiological effect with dramatically altered cellular function associated with carcinogenesis. Inhibition of miR-15b and miR-16 microRNA function leads to a ~1.2-1.4 fold increase in NOD1 protein concentration, with even slightly greater increases leading to ligand-independent, switch-like NOD1 activation. miRNA regulation of NOD1 is impaired in gastric cancer with a small increase being associated with greater early disease mortality. Overall, our data show that tight control of NOD1 expression by miRNA prevents this sensor from exceeding a physiological switching checkpoint that promotes persistent inflammation and lethal cancer progression, and reveal the impact of a single and modest cellular alteration on cancer.
2020-10-01 | GSE99550 | GEO