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A fat-enriched diet modifies intestinal microbiota and initiates a low-grade inflammation, insulin resistance and type-2 diabetes. Here, we demonstrate that before the onset of diabetes, after only one week of a high-fat diet (HFD), live commensal intestinal bacteria are present in large numbers in the adipose tissue and the blood where they can induce inflammation. This translocation is prevented in mice lacking the microbial pattern recognition receptors Nod1 or CD14, but overtly increased in Myd88 knockout and ob/ob mouse. This 'metabolic bacteremia' is characterized by an increased co-localization with dendritic cells from the intestinal lamina propria and by an augmented intestinal mucosal adherence of non-pathogenic Escherichia coli. The bacterial translocation process from intestine towards tissue can be reversed by six weeks of treatment with the probiotic strain Bifidobacterium animalis subsp. lactis 420, which improves the animals' overall inflammatory and metabolic status. Altogether, these data demonstrate that the early onset of HFD-induced hyperglycemia is characterized by an increased bacterial translocation from intestine towards tissues, fuelling a continuous metabolic bacteremia, which could represent new therapeutic targets.

Multiple innate immune sensors undergo rapid assembly into large complexes known as signalosomes. This is an essential step during cellular responses to microbes and danger signals. How this process is regulated to avoid accumulation of potentially toxic protein aggregates remains poorly understood. Abdel-Nour et al. identified a pathway, dependent on heme-regulated inhibitor, eukaryotic initiation factor 2α, activating transcription factor 4, and heat shock protein B8, which controls the folding and scaffolding of innate immune sensors, allowing optimal proinflammatory signaling (see the Perspective by Pierre). The pathway appears to mirror the endoplasmic reticulum unfolded protein response (UPR), and so was named the cytosolic UPR (cUPR). The cUPR may represent a general mechanism to control protein misfolding in cells. Science , this issue p. eaaw4144 ; see also p. 28 A cytosolic unfolded protein response controls the scaffolding and signaling of innate immune complexes Multiple cytosolic innate sensors form large signalosomes after activation, but this assembly needs to be tightly regulated to avoid accumulation of misfolded aggregates. We found that the eIF2α kinase heme-regulated inhibitor (HRI) controls NOD1 signalosome folding and activation through a process requiring eukaryotic initiation factor 2α (eIF2α), the transcription factor ATF4, and the heat shock protein HSPB8. The HRI/eIF2α signaling axis was also essential for signaling downstream of the innate immune mediators NOD2, MAVS, and TRIF but dispensable for pathways dependent on MyD88 or STING. Moreover, filament-forming α-synuclein activated HRI-dependent responses, which suggests that the HRI pathway may restrict toxic oligomer formation. We propose that HRI, eIF2α, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms, functionally homologous to the PERK/eIF2α/HSPA5 axis of the endoplasmic reticulum UPR.

Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis (ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH + breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increase the chemosensitivity of breast cancer by impairing BCSCs.

Macrophages are indispensable in homeostasis and innate immune responses in multiple tissues, while their polarization and functional characteristics are determined by the activating stimuli and their tissue microenvironment. The vitamin A derivative retinoic acid shows inhomogeneous distribution among the tissues and has an important modulatory role in inflammatory responses. However, its effects on the cytokine secretion induced by the cytosolic pattern-recognition receptors NOD1 and NOD2 are unclear. In our study, we used human monocyte-derived macrophages differentiated in the presence of GM-CSF or M-CSF to generate inflammation inducing (GM-MФ) or inflammation resolving (M-MФ) cells, respectively. We activated the cells with either a NOD1- or NOD2 specific agonist and, using ELISA, we determined the pattern and dynamics of cytokines secreted by the macrophage subpopulations. Furthermore, we studied the effect of all-trans retinoic acid (ATRA) pre-treatment on the NOD1- and NOD2-induced cytokine release. Our comparative analysis shows subpopulation-characteristic pattern of cytokine secretion, as GM-MФ produce significantly higher pro-inflammatory IL-6, IL-8, TNF-α and IL-1β, while M-MФ secret higher anti-inflammatory IL-10. However, IL-18 and IFNβ secretion was comparable between the MФ subpopulations. We also show for the first time that ATRA has marked impact on cytokine secretion triggered by NOD1 and NOD2. Importantly however, the ATRA-induced changes of cytokine secretion follow opposite tendency in two MФ subpopulations. In conclusion, these results show that NOD1/NOD2-induced cytokine secretion by macrophage subsets is highly context-dependent and our results highlight the importance of the retinoic acid content of the local tissue environment in shaping macrophage function in health and disease.

Helicobacter pylori is a bacterial pathogen that colonizes the human stomach, causing inflammation which, in some cases, leads to gastric ulcers and cancer. The clinical outcome of infection depends on a complex interplay of bacterial, host genetic, and environmental factors. Although H. pylori is recognized by both the innate and adaptive immune systems, this rarely results in bacterial clearance. Gastric epithelial cells are the first line of defense against H. pylori and alert the immune system to bacterial presence. Cytosolic delivery of proinflammatory bacterial factors through the cag type 4 secretion system ( cag -T4SS) has long been appreciated as the major mechanism by which gastric epithelial cells detect H. pylori . Classically attributed to the peptidoglycan sensor NOD1, recent work has highlighted the role of NOD1-independent pathways in detecting H. pylori ; however, the bacterial and host factors involved have remained unknown. Here, we show that bacterially derived heptose-1,7-bisphosphate (HBP), a metabolic precursor in lipopolysaccharide (LPS) biosynthesis, is delivered to the host cytosol through the cag -T4SS, where it activates the host tumor necrosis factor receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain (TIFA)-dependent cytosolic surveillance pathway. This response, which is independent of NOD1, drives robust NF-κB-dependent inflammation within hours of infection and precedes NOD1 activation. We also found that the CagA toxin contributes to the NF-κB-driven response subsequent to TIFA and NOD1 activation. Taken together, our results indicate that the sequential activation of TIFA, NOD1, and CagA delivery drives the initial inflammatory response in gastric epithelial cells, orchestrating the subsequent recruitment of immune cells and leading to chronic gastritis. IMPORTANCE H. pylori is a globally prevalent cause of gastric and duodenal ulcers and cancer. H. pylori antibiotic resistance is rapidly increasing, and a vaccine remains elusive. The earliest immune response to H. pylori is initiated by gastric epithelial cells and sets the stage for the subsequent immunopathogenesis. This study revealed that host TIFA and H. pylori -derived HBP are critical effectors of innate immune signaling that account for much of the inflammatory response to H. pylori in gastric epithelial cells. HBP is delivered to the host cell via the cag -T4SS at a time point that precedes activation of the previously described NOD1 and CagA inflammatory pathways. Manipulation of the TIFA-driven immune response in the host and/or targeting of ADP-heptose biosynthesis enzymes in H. pylori may therefore provide novel strategies that may be therapeutically harnessed to achieve bacterial clearance. H. pylori is a globally prevalent cause of gastric and duodenal ulcers and cancer. H. pylori antibiotic resistance is rapidly increasing, and a vaccine remains elusive. The earliest immune response to H. pylori is initiated by gastric epithelial cells and sets the stage for the subsequent immunopathogenesis. This study revealed that host TIFA and H. pylori -derived HBP are critical effectors of innate immune signaling that account for much of the inflammatory response to H. pylori in gastric epithelial cells. HBP is delivered to the host cell via the cag -T4SS at a time point that precedes activation of the previously described NOD1 and CagA inflammatory pathways. Manipulation of the TIFA-driven immune response in the host and/or targeting of ADP-heptose biosynthesis enzymes in H. pylori may therefore provide novel strategies that may be therapeutically harnessed to achieve bacterial clearance.

ILF preservation Isolated lymphoid follicles (ILFs) are areas of specialized lymphoid tissue found in the lining of the small intestine where they are involved in protecting the host from invading pathogens. A new study of the composition of ILFs and the factors required for their formation has found that they are induced in the mouse small intestine by the presence of peptidoglycan from Gram-negative bacteria via recognition by the NOD1 innate receptor in epithelia cells. ILFs range from clusters of a few B cells to well-organized lymphoid nodules. Once established, the ILFs exert control over the make-up of the bacterial community. This rare example of microbe-induced tissue genesis in mammals demonstrates how a constructive 'dialogue' between bacteria and host can contribute to efficient digestion and protection from intestinal pathogens. The generation of isolated lymphoid follicles is shown to depend on NOD1-induced responses to bacterial components. Isolated lymphoid follicles are in turn are shown to affect the composition of the host microbiota. Intestinal homeostasis is critical for efficient energy extraction from food and protection from pathogens. Its disruption can lead to an array of severe illnesses with major impacts on public health, such as inflammatory bowel disease characterized by self-destructive intestinal immunity. However, the mechanisms regulating the equilibrium between the large bacterial flora and the immune system remain unclear. Intestinal lymphoid tissues generate flora-reactive IgA-producing B cells, and include Peyer's patches and mesenteric lymph nodes, as well as numerous isolated lymphoid follicles (ILFs) 1 , 2 . Here we show that peptidoglycan from Gram-negative bacteria is necessary and sufficient to induce the genesis of ILFs in mice through recognition by the NOD1 (nucleotide-binding oligomerization domain containing 1) innate receptor in epithelial cells, and β-defensin 3- and CCL20-mediated signalling through the chemokine receptor CCR6. Maturation of ILFs into large B-cell clusters requires subsequent detection of bacteria by toll-like receptors. In the absence of ILFs, the composition of the intestinal bacterial community is profoundly altered. Our results demonstrate that intestinal bacterial commensals and the immune system communicate through an innate detection system to generate adaptive lymphoid tissues and maintain intestinal homeostasis.

( ), a zoonotic intracellular Gram-negative bacterium, is responsible for human infections presenting as flu-like fever and community-acquired pneumonia. Previous studies have implicated polymorphic membrane (Pmp) G in tissue tropism and induction of immune responses. However, the mechanisms by which Pmp19G promotes infection and immune evasion-especially via macrophage subversion remain poorly understood. This study demonstrates that both and recombinant -specific Pmp19G protein activated autophagy in macrophages. This activation was characterized by increased autophagosome formation, conversion of LC3-I to LC3-II, and accumulation of p62/SQSTM1, while lysosomal associated membrane protein 1 (LAMP1), a late autophagy biomarker, remained unaffected. Utilizing pull-down assays coupled with co-immunoprecipitation, we identified the NOD1 receptor as an interactor with the N-terminal domain of Pmp19G. Subsequent analysis confirmed activation of the NOD1-ATG16L1 signaling pathway. NOD1 knockout or knockdown significantly impaired Pmp19G-mediated autophagic flux. Furthermore, treatment with Pmp19G enhanced the recruitment of RAB7 during the late stages of autophagy. Our findings indicate that Pmp19G regulates macrophage autophagy through distinct mechanisms in early and late phases: activation of the NOD1-ATG16L1 signaling pathway initiates early autophagy, while enhanced RAB7 recruitment inhibits autophagosome-lysosome fusion during late autophagy. Collectively, Pmp19G-involved manipulation of the autophagic process represents a critical strategy employed by to evade host immune defenses, leading bacterial survival and spread.

Background and Aim Glioma is a highly aggressive malignancy of the central nervous system with a poor prognosis. The nucleoside‐binding oligomerization domain‐containing protein 1 (NOD1)/receptor‐interacting protein 2 (RIP2) pathway is involved in various inflammatory responses and is closely associated with microglial polarization. Microglial M2 polarization alters the glioma microenvironment, promoting tumor growth. This study aimed to investigate the role of the NOD1/RIP2 pathway in glioma progression. Methods We explored the mechanism of NOD1/RIP2 in glioma progression through bioinformatics analysis, clinical sample evaluation, and in vivo and in vitro experiments. Bioinformatics analysis was conducted to assess NOD1 expression in glioma tissues. Multiparameter MRI and histologic analyses were performed on human tissues, and the correlation between the relative apparent diffusion coefficient (rADC) and NOD1 expression was analyzed. C6 and U251 glioma cells were treated with ML130, a NOD1 inhibitor, and assessed using 5‐ethynyl‐2′‐deoxyuridine (EdU), plate cloning, Transwell, and wound healing assays. Key molecules of the NOD1/RIP2 pathway were examined through immunofluorescence and Western blotting. Quantitative real‐time polymerase chain reaction (qRT‐PCR) was used to detect Arg1 and CD206 expression in BV2 mouse microglia cultured with C6‐derived conditioned medium (CM). The changes in glioma cell biologic behavior were assessed using C6/BV2‐derived CM through EdU, wound healing, and Transwell assays. Finally, the role and mechanism of NOD1 in glioma growth were evaluated using a rat glioma model. Results Bioinformatics analysis showed that NOD1 was highly expressed in glioma tissues and strongly correlated with glioma grade. Human brain glioma samples exhibited increased expression of NOD1, RIP2, Iba1, interleukin‐1β, and CD206, with higher expression in high‐grade gliomas compared to low‐grade gliomas. The NOD1 expression was negatively correlated with rADC values. Treatment with ML130 inhibited glioma cell proliferation, migration, and invasion while reducing NOD1 and RIP2 expression. The expression levels of Arg1 and CD206 in BV2 cells cultured with C6‐derived CM decreased in both ML130 and GSK‐583 groups, while the expression levels increased in the ie‐DAP group. Compared with the control group, the expressions of Arg1 and CD206 in microglia in the GSK‐583 + ML130 and GSK‐583 + ie‐DAP groups were inhibited, and the inhibitory effect in the GSK‐583 + ML130 group was more significant. Furthermore, after culturing with C6/BV2 derived CM, the activity of C6 cells was significantly inhibited in the ML130 group, while the activity increased in the ie‐DAP group. The activity of C6 cells in the GSK‐583 + ML130 and GSK‐583 + ie‐DAP groups was significantly decreased, and this effect was more pronounced in the GSK‐583 + ML130 group. ML130‐treated glioma‐bearing rats exhibited reduced tumor growth, suppressed NOD1/RIP2 pathway activation, and inhibited microglial M2 polarization. However, the results observed in the ie‐DAP group were opposite. Conclusions NOD1 is an effective predictor of preoperative glioma grade and prognosis. It facilitates glioma progression by promoting microglial M2 polarization through the NOD1/RIP2 pathway. NOD1 is an effective predictor of preoperative glioma grade and prognosis. It facilitates glioma progression by promoting microglial M2 polarization via the NOD1/RIP2 pathway.

Background Metastatic cervical squamous cell carcinoma (CSCC) has poor prognosis and is recalcitrant to the current treatment strategies, which warrants the necessity to identify novel prognostic markers and therapeutic targets. Given that CSCC is a virus-induced malignancy, we hypothesized that the pattern recognition receptors (PRRs) involved in the innate immune response likely play a critical role in tumor development. Methods A bioinformatics analysis, qPCR, IHC, immunofluorescence, and WB were performed to determine the expression of NOD1/NOD2. The biological characteristics of overexpression NOD1 or NOD2 CSCC cells were compared to parental cells: proliferation, migration/invasion and cytokines secretion were examined in vitro through CCK8/colony formation/cell cycle profiling/cell counting, wound healing/transwell, and ELISA assays, respectively. The proliferative and metastatic capacity of overexpression NOD1 or NOD2 CSCC cells were also evaluated in vivo. FCM, mRNA and protein arrays, ELISA, and WB were used to identify the mechanisms involved, while novel pharmacological treatment were evaluated in vitro and in vivo. Quantitative variables between two groups were compared by Student’s t test (normal distribution) or Mann-Whitney U test (non-normal distribution), and one-way or two-way ANOVA was used for comparing multiple groups. Pearson χ 2 test or Fisher’s exact test was used to compare qualitative variables. Survival curves were plotted by the Kaplan-Meier method and compared by the log-rank test. P values of < 0.05 were considered statistically significant. Results NOD1 was highly expressed in CSCC with lymph-vascular space invasion (LVSI, P < 0.01) and lymph node metastasis (LM, P < 0.01) and related to worse overall survival (OS, P = 0.016). In vitro and in vivo functional assays revealed that the upregulation of NOD1 or NOD2 in CSCC cells promoted proliferation, invasion, and migration. Mechanistically, NOD1 and NOD2 exerted their oncogenic effects by activating NF-κb and ERK signaling pathways and enhancing IL-8 secretion. Inhibition of the IL-8 receptor partially abrogated the effects of NOD1/2 on CSCC cells. Conclusions NOD1/2-NF-κb/ERK and IL-8 axis may be involved in the progression of CSCC; the NOD1 significantly enhanced the progression of proliferation and metastasis, which leads to a poor prognosis. Anti-IL-8 was identified as a potential therapeutic target for patients with NOD1 high tumor.

NOD1 is an innate immune sensor playing an important role in fighting against infection. However, its role in cancer is far from being clarified, and whether NOD1 plays a role in the progression of hepatocellular carcinoma (HCC) has never been reported. Here, we found that NOD1 expression was significantly decreased in hepatocellular carcinoma tissues and overexpression of NOD1 significantly inhibited tumorigenesis in vivo. In vitro experiments demonstrated that NOD1 inhibited proliferation of HCC cells by directly targeting proto-oncogene SRC and inducing cell cycle arrest at G1 phase. Further investigation showed that NOD1 exerted its antitumor effect by inhibiting SRC activation and further suppressing SRC/MAPK axis in hepatocellular carcinoma cells. Moreover, NOD1 dramatically enhanced the response of HCC cells to chemotherapy via inhibition of SRC-MAPK axis both in vitro and in vivo. Collectively, these data indicated that NOD1 suppressed proliferation and enhanced response to sorafenib or 5-FU treatment through inhibiting SRC-MAPK axis in hepatocellular carcinoma.Key messagesNOD1 significantly inhibited tumorigenesis of HCC in cellular and animal models.NOD1 inhibited proliferation of HCC cells by inducing cell cycle arrest.NOD1 exerted its antitumor effect on HCC by directly interacting with SRC and inhibiting SRC-MAPK axis.NOD1 significantly enhanced the chemosensitivity of HCC cells to chemotherapeutic drugs.