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Immune surveillance of cellular homeostasis by NOD1/2 via sensing cytosolic sphingosine-1-phosphate (S1P)

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124828 | GEO | 2020/01/01

REPOSITORIES: GEO

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Project description:Characterization of NWD1; a novel NLR-related protein and further correlate it as a putative Prostate Cancer marker. NLRs (NACHT and Leucine Rich Repeat domain containing proteins) constitute a major subfamily of innate immunity proteins mostly acting as cytosolic pattern recognition receptors (PRRs), involved in the detection of cytoplasmic pathogen-associated molecular patterns (PAMPs) and endogenous danger signals. The recognition of the signals initiates a variety of host defense pathways through the activation of NF-kappaB, stress kinases, interferon response factors (IRFs) and/or inflammatory caspases. Despite the importance in host immune response, deregulation on NLR activities has been described in a variety of maladies, including chronic inflammation and cancer predisposition. For instance, NOD1 was one of the first NLR members shown to possibly play a role in tumorigenesis, since NOD1 stimulation induces apoptosis in MCF-7 breast carcinoma cells, and NOD1-/- MCF-7 cells generate larger tumors after injection in SCID mice. Mice deficient in NLR member NLRP3, and/or its interacting partners ASC or caspase-1, are also shown to be more susceptible to colitis-associated cancer (CAC). Polymorphisms along NLR genes NOD1 and NOD2 have also been correlated with altered cancer risk. NOD1 SNPs have been associated with gastric cancer, lymphoma, ovarian, prostate, and lung cancer due to the recognition of H. pylori (etiologic agent in gastric cancer and MALT lymphoma), C. trachomatis (putative etiologic agent in ovarian cancer), P. acnes (possible causative agent in PCa) and C. pneumonia (plausible etiological agent in lung cancer) as NOD1 ligands. Particularly, NOD1 and NOD2 have been shown to be fully operative in prostate epithelial cells and, in cooperation with TLRs, may elicit immune response during PCa progression. To access a tissue-specific gene expression profile for NWD1, quantitative PCR analysis was performed using a normalized cDNA panel derived from 48 human tissues (TissueScan Tissue qPCR Array, Origene). Two apparently independent expression patterns were detected, respectively related to neurological related organs (brain, pituitary and retina) and male reproductive system (prostate, epididymis and testis), where the highest mRNA levels was observed in prostate tissue. Results were confirmed using a second set of NWD1-specific qPCR primers (data not shown). Moreover, a similar expression pattern was virtually observed using the SAGE database from the Cancer Genome Anatomy Project (CGAP) of the National Cancer Institute (not shown). Comparative gene expression microarray data was analyzed systematically by Ingenuity Pathway Analysis (IPA) to set up potential networks based on NWD1 regulated genes. The eventual participation of NWD1 in signaling transduction pathways was further examined by microarray analysis (Human WG-6v3 Expression BeadChip, Illumina) comparing the expression profile of PPC-1 cells lacking NWD1 expression (sh184 & sh3922) versus control cells (shGFP). According to the differential expression profile that was generated and analyzed by the Ingenuity PathwaysTM software (IPA version 7.1, Ingenuity Systems), NWD1 is presumably associated with biological networks related, for instance, to tissue morphology, organogenesis, cancer and neurological diseases .

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Immune surveillance of cellular homeostasis by NOD1/2 via sensing cytosolic sphingosine-1-phosphate (S1P)

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