The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and ...induce proinflammatory and antimicrobial responses. Here, we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochemical analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies have suggested several mechanisms to account for the link between NOD2 variants and susceptibility to Crohn’s disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders.
The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 sense conserved motifs in bacterial peptidoglycan and induce proinflammatory and antimicrobial responses. Núñez and colleagues examine NOD1 and NOD2 activation, the regulation of their signaling pathways, and their role in host defense and inflammatory disease.
A dense resident microbial community in the gut, referred as the commensal microbiota, coevolved with the host and is essential for many host physiological processes that include enhancement of the ...intestinal epithelial barrier, development of the immune system and acquisition of nutrients. A major function of the microbiota is protection against colonization by pathogens and overgrowth of indigenous pathobionts that can result from the disruption of the healthy microbial community. The mechanisms that regulate the ability of the microbiota to restrain pathogen growth are complex and include competitive metabolic interactions, localization to intestinal niches and induction of host immune responses. Pathogens, in turn, have evolved strategies to escape from commensal-mediated resistance to colonization. Thus, the interplay between commensals and pathogens or indigenous pathobionts is critical for controlling infection and disease. Understanding pathogen-commensal interactions may lead to new therapeutic approaches to treating infectious diseases.
The activator and composition of the NLRP6 inflammasome remain poorly understood. We find that lipoteichoic acid (LTA), a molecule produced by Gram-positive bacteria, binds and activates NLRP6. In ...response to cytosolic LTA or infection with Listeria monocytogenes, NLRP6 recruited caspase-11 and caspase-1 via the adaptor ASC. NLRP6 activation by LTA induced processing of caspase-11, which promoted caspase-1 activation and interleukin-1β (IL-1β)/IL-18 maturation in macrophages. Nlrp6−/− and Casp11−/− mice were less susceptible to L. monocytogenes infection, which was associated with reduced pathogen loads and impaired IL-18 production. Administration of IL-18 to Nlrp6−/− or Casp11−/− mice restored the susceptibility of mutant mice to L. monocytogenes infection. These results reveal a previously unrecognized innate immunity pathway triggered by cytosolic LTA that is sensed by NLRP6 and exacerbates systemic Gram-positive pathogen infection via the production of IL-18.
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•LTA from Gram-positive bacteria binds and activates NLRP6•Listeria and cytosolic LTA induce caspase-11 processing via NLRP6 and ASC•Processed caspase-11 promotes caspase-1 activation and IL-18 secretion•NLRP6 and caspase-11 exacerbate Gram-positive pathogen infection in vivo
Lipoteichoic acid produced by Gram-positive bacteria is sensed by the NLRP6 inflammasome and leads to the processing of both caspase-1 and caspase-11, exacerbating infection.
Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing ...(IL-11
) cells are not fully understood. To characterize IL-11
cells in vivo, we generate Il11 reporter mice. IL-11
cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11
cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11
fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11
fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.
The precise mechanism by which oral infection contributes to the pathogenesis of extra-oral diseases remains unclear. Here, we report that periodontal inflammation exacerbates gut inflammation ...in vivo. Periodontitis leads to expansion of oral pathobionts, including Klebsiella and Enterobacter species, in the oral cavity. Amassed oral pathobionts are ingested and translocate to the gut, where they activate the inflammasome in colonic mononuclear phagocytes, triggering inflammation. In parallel, periodontitis results in generation of oral pathobiont-reactive Th17 cells in the oral cavity. Oral pathobiont-reactive Th17 cells are imprinted with gut tropism and migrate to the inflamed gut. When in the gut, Th17 cells of oral origin can be activated by translocated oral pathobionts and cause development of colitis, but they are not activated by gut-resident microbes. Thus, oral inflammation, such as periodontitis, exacerbates gut inflammation by supplying the gut with both colitogenic pathobionts and pathogenic T cells.
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•Oral inflammation triggers expansion of oral pathobionts•Ectopic gut colonization by oral pathobionts promotes colitis through IL-1β•Oral Th17 cells that arise during oral inflammation can migrate to the gut•Oral pathobiont-reactive Th17 cells that migrate to the gut contribute to colitis
Periodontitis leads to expansion of pathobiont members of the oral microbiota, which promote colitis via colonization of the gut as well as induction of migratory Th17 cells, constituting a dual microbiome and immune mechanism linking oral and gut health.
The gut microbiota is compartmentalized in the intestinal lumen and induces local immune responses, but it remains unknown whether the gut microbiota can induce systemic response and contribute to ...systemic immunity. We report that selective gut symbiotic gram-negative bacteria were able to disseminate systemically to induce immunoglobulin G (IgG) response, which primarily targeted gram-negative bacterial antigens and conferred protection against systemic infections by E. coli and Salmonella by directly coating bacteria to promote killing by phagocytes. T cells and Toll-like receptor 4 on B cells were important in the generation of microbiota-specific IgG. We identified murein lipoprotein (MLP), a highly conserved gram-negative outer membrane protein, as a major antigen that induced systemic IgG homeostatically in both mice and humans. Administration of anti-MLP IgG conferred crucial protection against systemic Salmonella infection. Thus, our findings reveal an important function for the gut microbiota in combating systemic infection through the induction of protective IgG.
•Gut microbiota induces homeostatic IgG response to commensal antigens•Homeostatic commensal-specific IgG antibodies recognize gram-negative antigens•Commensal-specific IgG opsonizes pathogens to mediate clearance•Gram-negative murein lipoprotein (MLP) is a major commensal antigen for IgG response
It is not clear whether gut microbiota can induce systemic responses. Nunez and colleagues find that the gut microbiota induces the generation of IgG antibodies under homeostatic conditions. These IgG antibodies mainly recognize gram-negative commensal antigens and confer protection against systemic infection by targeting conserved antigens on pathogens.
NOD (nucleotide-binding oligomerization domain) proteins are members of a family that includes the apoptosis regulator APAF1 (apoptotic protease activating factor 1), mammalian NOD-LRR (leucine-rich ...repeat) proteins and plant disease-resistance gene products. Several NOD proteins have been implicated in the induction of nuclear factor-kappaB (NF-kappaB) activity and in the activation of caspases. Two members of the NOD family, NOD1 and NOD2, mediate the recognition of specific bacterial components. Notably, genetic variation in the genes encoding the NOD proteins NOD2, cryopyrin and CIITA (MHC class II transactivator) in humans and Naip5 (neuronal apoptosis inhibitory protein 5) in mice is associated with inflammatory disease or increased susceptibility to bacterial infections. Mammalian NOD proteins seem to function as cytosolic sensors for the induction of apoptosis, as well as for innate recognition of microorganisms and regulation of inflammatory responses.
Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial populations and for host health. ...How symbiotic relationships between hosts and native microbes persist during times of iron limitation is unclear. Here, we demonstrate that indigenous bacteria possess an iron-dependent mechanism that inhibits host iron transport and storage. Using a high-throughput screen of microbial metabolites, we found that gut microbiota produce metabolites that suppress hypoxia-inducible factor 2α (HIF-2α) a master transcription factor of intestinal iron absorption and increase the iron-storage protein ferritin, resulting in decreased intestinal iron absorption by the host. We identified 1,3-diaminopropane (DAP) and reuterin as inhibitors of HIF-2α via inhibition of heterodimerization. DAP and reuterin effectively ameliorated systemic iron overload. This work provides evidence of intestine-microbiota metabolic crosstalk that is essential for systemic iron homeostasis.
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•Lactobacillus species sense intestinal iron levels and attenuate host iron absorption•Microbial metabolites DAP and reuterin are novel HIF-2α inhibitors•Gut microbial metabolites regulate intestinal iron storage via ferritin regulation•Gut microbiota can be therapeutically targeted for iron-related disorders
Das et al. show that gut microbiota regulate host iron metabolism. Lactobacillus species are the major bacterial players involved in sensing intestinal iron levels and attenuating host iron absorption. The authors further show that mammalian iron disorders can be therapeutically targeted by modulating microbial species or their metabolites.
Nods are cytosolic proteins that contain a nucleotide-binding oligomerization domain (NOD). These proteins include key regulators of apoptosis and pathogen resistance in mammals and plants. A large ...number of Nods contain leucine-rich repeats (LRRs), hence referred to as NOD-LRR proteins. Genetic variation in several NOD-LRR proteins, including human Nod2, Cryopyrin, and CIITA, as well as mouse Naip5, is associated with inflammatory disease or increased susceptibility to microbial infections. Nod1, Nod2, Cryopyrin, and Ipaf have been implicated in protective immune responses against pathogens. Together with Toll-like receptors, Nod1 and Nod2 appear to play important roles in innate and acquired immunity as sensors of bacterial components. Specifically, Nod1 and Nod2 participate in the signaling events triggered by host recognition of specific motifs in bacterial peptidoglycan and, upon activation, induce the production of proinflammatory mediators. Naip5 is involved in host resistance to Legionella pneumophila through cell autonomous mechanisms, whereas CIITA plays a critical role in antigen presentation and development of antigen-specific T lymphocytes. Thus, NOD-LRR proteins appear to be involved in a diverse array of processes required for host immune reactions against pathogens.
The benefits of commensal bacteria to the health of the host have been well documented, such as providing stimulation to potentiate host immune responses, generation of useful metabolites, and direct ...competition with pathogens. However, the ability of the host immune system to control the microbiota remains less well understood. Recent microbiota analyses in mouse models have revealed detailed structures and diversities of microbiota at different sites of the digestive tract in mouse populations. The contradictory findings of previous studies on the role of host immune responses in overall microbiota composition are likely attributable to the high β-diversity in mouse populations as well as technical limitations of the methods to analyze microbiota. The host employs multiple systems to strictly regulate their interactions with the microbiota. A spatial segregation between the host and microbiota is achieved with the mucosal epithelium, which is further fortified with a mucus layer on the luminal side and Paneth cells that produce antimicrobial peptides. When commensal bacteria or pathogens breach the epithelial barrier and translocate to peripheral tissues, the host immune system is activated to eliminate them. Defective segregation and tissue elimination of commensals result in exaggerated inflammatory responses and possibly death of the host. In this review, we discuss the current understanding of mouse microbiota, its common features with human microbiota, the technologies utilized to analyze microbiota, and finally the challenges faced to delineate the role of host immune responses in the composition of the luminal microbiota.
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