DOCSLIB.ORG

Nod2 Influences Microbial Resilience and Susceptibility to Colitis Following

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Nod2 Influences Microbial Resilience and Susceptibility to Colitis Following www.nature.com/mi ARTICLE Nod2 influences microbial resilience and susceptibility to colitis following antibiotic exposure A. Goethel1,2, W. Turpin2,3, S. Rouquier3, G. Zanello3, S. J. Robertson1, C. J. Streutker4, D. J. Philpott1 and K. Croitoru1,2,3,5 Inflammatory bowel disease (IBD) etiology involves genetic susceptibility, environmental triggers, and the gut microbiome. Antibiotic exposure is associated with IBD, both in early life and adulthood. Here, we investigated whether Nod2-deficiency influenced response of the gut microbiota to antibiotics and subsequent colitis susceptibility. Wild-type and Nod2−/− littermate mice were treated with amoxicillin as adults or neonates, and fecal samples were collected for 16S rRNA sequencing. Five weeks after antibiotic exposure, dextran sulfate sodium (DSS) colitis was induced. Antibiotic treatment altered the microbiota of adult WT and Nod2−/− mice, but recovery was delayed in Nod2−/− mice. Neonatal antibiotic treatment significantly changed the microbiota at weaning in WT and Nod2−/− littermates; however, Nod2−/− mice maintained reduced microbial diversity 14 days after cessation of antibiotics. Although treatment of adult mice did not influence susceptibility to colitis, neonatally treated Nod2−/− mice developed a more severe colitis. Moreover, the colitis phenotype was transferable through fecal transplantation into germ-free Nod2−/− recipients, and was associated with changes in intestinal T cells and the cytokine milieu following inflammation. These data demonstrate that neonatal antibiotic exposure has long-lasting influence on the microbiota and mucosal immunity, and may explain how NOD2 contributes to the risk of intestinal inflammation. Mucosal Immunology (2019) 12:720–732; https://doi.org/10.1038/s41385-018-0128-y INTRODUCTION sustained alterations of the gut microbiota following neonatal The mammalian gut typically harbors multiple types of microbes, antibiotic exposure combined with the absence of Nod2 signaling including ~4 × 1013 bacteria,1 in a dynamic community whose during mucosal barrier breach results in exacerbated mucosal structure depends on environmental and host genetic influ- damage. ences.2–6 Maintaining this symbiotic relationship is key to the balance between health and disease. Colonization of the gut microbiota during neonatal life influences the development of the RESULTS mucosal immune system.7 Environmental perturbations during Nod2 genotype influences microbiota resilience after antibiotic this critical window can alter the ‘normal’ development of the gut exposure in adult mice microbiota and the mucosal immune system, possibly increasing We first investigated how a single course of the broad-spectrum susceptibility to disease. Indeed, mouse and human studies antibiotic, amoxicillin, altered the adult murine microbiota, and suggest that neonatal antibiotic exposure is associated with an whether Nod2 genotype influenced this perturbation. Adult WT increased risk of inflammatory diseases, including asthma,8 and Nod2−/− littermate mice were given amoxicillin- obesity9, and inflammatory bowel disease (IBD).10–12 This is supplemented water for 7 days and stool samples were collected supported by observations that early life and repeated antibiotic at day 0 (pre-treatment) and on day 7 (Fig. 1a). In order to further exposure significantly increases the risk for developing IBD.11,13 assess whether Nod2 influenced the resilience or recovery of the Given that Nod2 mutations are one of the most important microbiota following antibiotic exposure, stool was collected on genetic risks for the development of Crohn’s disease, we day 21, i.e., 14 days after stopping antibiotic-supplemented water. investigated whether Nod2-deficiency altered the impact of Each mouse was compared to its pre-treatment composition antibiotic exposure on microbiota composition and susceptibility (day 0) and water-treated littermate controls. Using 16S rDNA to colitis. We found that Nod2 influenced microbial resilience sequencing, microbial diversity was evaluated for species richness following adult and neonatal antibiotic treatment. Although the (as measured by the Chao1 rarefaction index) and beta diversity adult treatment did not alter colitis susceptibility, neonatal (as measured by Bray–Curtis dissimilarity, which factors in antibiotic treatment resulted in increased colitis severity in presence/absence and relative abundance of operational taxo- Nod2−/− mice. Moreover, transfer of the neonatal antibiotic- nomic units). microbiota increased colitis severity in germ-free recipients. This As previously described,14 Nod2 genotype was not associated phenotype was associated with altered cytokines and increased with any difference in the microbiota in terms of species richness, colonic Gata3+Foxp3+ regulatory T cells. This suggests that the beta diversity, or composition at day 0 (Fig. 1b–d), indicating that 1Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; 2Zane Cohen Centre for Digestive Diseases, The Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5T 3L9, Canada; 3Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; 4St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada and 5Division of Gastroenterology, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada Correspondence: K Croitoru ([email protected]) Received: 9 September 2018 Revised: 5 December 2018 Accepted: 16 December 2018 Published online: 16 January 2019 © Society for Mucosal Immunology 2019 Nod2 influences microbial resilience and susceptibility to colitis. A Goethel et al. 721 ab WT Water Water 300 WT Water Nod2–/– Water Water ** * Nod2–/– Water WT Abx Water 200 WT + Abx Day 0 –/– Abx Water *** *** WT + Abx Day 7 Nod2 WT + Abx Day 21 Chao1 index 100 Nod2–/– + Abx Day 0 Day 0 7 Nod2–/– + Abx Day 7 21 –/– Age (w) Nod2 + Abx Day 21 8 9 11 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10,000 Sequences per sample c Day 0 Day 7 Day 21 0.3 0.4 0.3 0.2 0.3 0.2 0.2 0.1 0.1 0.1 0.0 0.0 0.0 –0.1 –0.1 –0.1 –0.2 WT –0.2 Nod2–/– –0.2 –0.3 –0.3 WT + Abx Nod2–/– + Abx –0.4 –0.4 –0.3 –0.20 –0.15 –0.10 –0.05 0.00 0.05 –0.4 –0.2 0.0 0.2 0.4 0.6 0.8 –0.20 –0.15 –0.10 –0.05 0.00 0.05 0.10 0.15 0.20 0.25 PC2 11.8% PC1 28.1% d f –2 –1 0 1 2 Row Z-Score Lactobacillus 1234567890();,: Undefined_clostridiales 10000100 Allobaculum Oscillospira Family Undefined_rikenellaceae Ruminococcus_lachnospiraceae Other Undefined_ruminococcaceae Verrucomicrobiaceae Aldercreutzia Bifidobacterium Enterobacteriaceae Turicibacter Desulfovibrionaceae Ruminococcus_ruminococcaceae Coprococcus Erysipelotrichaceae Undefined_lachnospiraceae Ruminococcaceae Undefined_clostridiaceae Lachnospiraceae Odoribacter Desulfovibrio Clostridiales_unspecified Undefined_F16 Lactobacillaceae Sutterella [Paraprevotellaceae] Dorea Undefined_erysipelotrichaceae S24-7 Undefined_christensenellaceae Rikenellaceae Undefined_RF32 Prevotellaceae Undefined_mogibacteriaceae Clostridium Relative Abundance (%) Bacteroidaceae Undefined_helicobacteraceae Bacteroidales_unspecified Undefined_enterobacteriaceae Coriobacteriaceae Dehalobacterium Parabacteroides Bifidobacteriaceae Undefined_enterobacteriaceae Undefined_lachnospiraceae 0 Akkermansia Bacteroides –/– –/– –/– Undefined_S24-7 WT WT WT Nod2 Nod2 Nod2 –/– Day 0721 WT Nod2 + Abx: d7 + Abx: d0 + Abx: d21 e –/– WT Nod2 –/– –/– –/– WT + Abx: d7 WT + Abx: d0 22 Bilophila Bacteroides WT + Abx: d21 Nod2 Bacteroidaceae Nod2 21 Bacteroides * Enterobacteriales Nod2 20 Bacteroidaceae * Enterobacteriaceae Bilophila 19 Allobaculum * Clostridium 18 Erysipelotrichi * Desulfovibrionaceae_unspecified 17 * Enterobacteriaceae_unspecified Erysipelotrichales * Gammaproteobacteria 16 Erysipelotrichaceae Allobaculum 15 Rikenellaceae Erysipelotrichaceae 14 Rikenellaceae_unspecified Erysipelotrichi 13 Erysipelotrichales Candidatus Arthomitus Rikenellaceae 12 Odoribacter Rikenellaceae_unspecified 11 Odoribacteraceae Odoribacteraceae 10 Odoribacter RF32 Desulfovibrio 9 F16 F16_unspecified 8 F16_unspecified TM7 7 TM7_3 TM7_3 F16 6 Alphaproteobacteria Mogibacteriaceae * 5 CW040 Mogibacteriaceae_unspecified * Alphaproteobacteria 4 RF32_unspecified Candidatus Arthomitus 3 TM7 RF32_unspecified 2 Desulfovibrio RF32 1 CW040 46 –6 –4 –2 0 2 4 6 –6 –4 –2 0 2 LDA score (log 10) LDA score (log 10) Nod2-deficiency alone was not sufficient to alter microbial (Fig. 1b, c). This was characterized by reduced species richness colonization. Antibiotic treatment shifted the microbial commu- (Fig. 1b), and loss of taxa including Erysipelotrichaceae, Clos- nity away from pre-treatment composition in both WT (R = 0.6778, tridiales, and Lactobacillaceae, with corresponding increases in p = 0.001) and Nod2−/− (R = 0.7922, p = 0.001) littermates at day 7 Enterobacteriaceae and Bacteroidaceae (Fig. 1d). Thus, the Mucosal Immunology (2019) 12:720 – 732 Nod2 influences microbial resilience and susceptibility to colitis. A Goethel et al. 722 Fig. 1 Nod2 genotype influences microbiota resilience after antibiotic exposure in adult mice. a Experimental strategy. Starting at 8 weeks of age, littermate WT and Nod2−/− mice received either water or antibiotic (Abx) treatment for 7 days followed by 2 weeks of water to allow for microbial recovery. Arrows indicate time points of stool collection for sequencing. b Species richness at day 0, 7, and 21 as measured by the Chao1 rarefaction index. c Principal coordinates plot of Bray–Curtis dissimilarity for each time point. Each dot represents one mouse. (ANOSIM, WT+Abx d0 vs. 7: R = 0.6778,
Load more

Recommended publications
  • The Expression of NOD2, NLRP3 and NLRC5 and Renal Injury in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
    Wang et al. J Transl Med (2019) 17:197 https://doi.org/10.1186/s12967-019-1949-5 Journal of Translational Medicine RESEARCH Open Access The expression of NOD2, NLRP3 and NLRC5 and renal injury in anti-neutrophil cytoplasmic antibody-associated vasculitis Luo‑Yi Wang1,2,3, Xiao‑Jing Sun1,2,3, Min Chen1,2,3* and Ming‑Hui Zhao1,2,3,4 Abstract Background: Nucleotide‑binding oligomerization domain (NOD)‑like receptors (NLRs) are intracellular sensors of pathogens and molecules from damaged cells to regulate the infammatory response in the innate immune system. Emerging evidences suggested a potential role of NLRs in anti‑neutrophil cytoplasmic antibody (ANCA)‑associated vasculitis (AAV). This study aimed to investigate the expression of nucleotide‑binding oligomerization domain con‑ taining protein 2 (NOD2), NOD‑like receptor family pyrin domain containing 3 (NLRP3) and NOD‑like receptor family CARD domain containing 5 (NLRC5) in kidneys of AAV patients, and further explored their associations with clinical and pathological parameters. Methods: Thirty‑four AAV patients in active stage were recruited. Their renal specimens were processed with immu‑ nohistochemistry to assess the expression of three NLRs, and with double immunofuorescence to detect NLRs on intrinsic and infltrating cells. Analysis of gene expression was also adopted in cultured human podocytes. The associa‑ tions between expression of NLRs and clinicopathological parameters were analyzed. Results: The expression of NOD2, NLRP3 and NLRC5 was signifcantly higher in kidneys from AAV patients than those from normal controls, minimal change disease or class IV lupus nephritis. These NLRs co‑localized with podocytes and infltrating infammatory cells.
    [Show full text]
  • Genetic Variation in Pattern-Recognition Receptors and Association with Leprosy 145
    DOI: 10.5772/intechopen.73871 ProvisionalChapter chapter 8 Genetic Variation inin Pattern-RecognitionPattern-Recognition ReceptorsReceptors and and Association withwith LeprosyLeprosy Karina Talita de Oliveira Santana JorgeJorge andand Frederico Marianetti SorianiSoriani Additional information isis available atat thethe endend ofof thethe chapterchapter http://dx.doi.org/10.5772/intechopen.73871 Abstract Mycobacterium leprae is a highly infectious and low pathogenic microorganism that is the causal agent of leprosy. The differences in vulnerability to leprosy, the spectral immune response, and the clinical manifestations of this disease are related to different genetic backgrounds among individuals. In this sense, genetic variants, especially in genes related to mycobacteria recognition and host immune response, may be key factors to explain individual susceptibility and resistance to leprosy and their conditions. In this chapter, studies regarding association of genetic variants in pattern-recognition receptors (PRRs) and leprosy will be reviewed revealing the importance of molecules such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in leprosy initiation and maintenance. Keywords: polymorphisms, pattern-recognition receptors, mycobacterium leprae, leprosy 1. Introduction Leprosy is caused by Mycobacterium leprae, which is an intracellular bacterium with high infectivity and low pathogenicity. It means that there are a large number of people exposed to this pathogen; however, the majority of them are naturally resistant. On the other hand, some people develop leprosy once challenged with M. leprae. The people who develop disease may present different clinical forms of leprosy. Some of them develop a localized disease, named tuberculoid leprosy, with a strong host response, which does not avoid development of nerve injury and physical disabilities.
    [Show full text]
  • Cytotoxic T Cells Class I- Dependent Lymphocyte Killing by NLRC5 Deficiency Selectively Impairs
    The Journal of Immunology NLRC5 Deficiency Selectively Impairs MHC Class I- Dependent Lymphocyte Killing by Cytotoxic T Cells Francesco Staehli,* Kristina Ludigs,* Leonhard X. Heinz,† Queralt Seguı´n-Este´vez,‡ Isabel Ferrero,x Marion Braun,x Kate Schroder,{ Manuele Rebsamen,† Aubry Tardivel,* Chantal Mattmann,* H. Robson MacDonald,x Pedro Romero,x Walter Reith,‡ Greta Guarda,*,1 and Ju¨rg Tschopp*,1,2 Nucleotide-binding oligomerization domain-like receptors (NLRs) are intracellular proteins involved in innate-driven inflamma- tory responses. The function of the family member NLR caspase recruitment domain containing protein 5 (NLRC5) remains a matter of debate, particularly with respect to NF-kB activation, type I IFN, and MHC I expression. To address the role of NLRC5, we generated Nlrc5-deficient mice (Nlrc5D/D). In this article we show that these animals exhibit slightly decreased CD8+ T cell percentages, a phenotype compatible with deregulated MHC I expression. Of interest, NLRC5 ablation only mildly affected MHC I expression on APCs and, accordingly, Nlrc5D/D macrophages efficiently primed CD8+ T cells. In contrast, NLRC5 deficiency dramatically impaired basal expression of MHC I in T, NKT, and NK lymphocytes. NLRC5 was sufficient to induce MHC I expression in a human lymphoid cell line, requiring both caspase recruitment and LRR domains. Moreover, endogenous NLRC5 localized to the nucleus and occupied the proximal promoter region of H-2 genes. Consistent with downregulated MHC I expression, the elimination of Nlrc5D/D lymphocytes by cytotoxic T cells was markedly reduced and, in addition, we observed low NLRC5 expression in several murine and human lymphoid-derived tumor cell lines.
    [Show full text]
  • Post-Transcriptional Inhibition of Luciferase Reporter Assays
    THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 34, pp. 28705–28716, August 17, 2012 © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Post-transcriptional Inhibition of Luciferase Reporter Assays by the Nod-like Receptor Proteins NLRX1 and NLRC3* Received for publication, December 12, 2011, and in revised form, June 18, 2012 Published, JBC Papers in Press, June 20, 2012, DOI 10.1074/jbc.M111.333146 Arthur Ling‡1,2, Fraser Soares‡1,2, David O. Croitoru‡1,3, Ivan Tattoli‡§, Leticia A. M. Carneiro‡4, Michele Boniotto¶, Szilvia Benko‡5, Dana J. Philpott§, and Stephen E. Girardin‡6 From the Departments of ‡Laboratory Medicine and Pathobiology and §Immunology, University of Toronto, Toronto M6G 2T6, Canada, and the ¶Modulation of Innate Immune Response, INSERM U1012, Paris South University School of Medicine, 63, rue Gabriel Peri, 94276 Le Kremlin-Bicêtre, France Background: A number of Nod-like receptors (NLRs) have been shown to inhibit signal transduction pathways using luciferase reporter assays (LRAs). Results: Overexpression of NLRX1 and NLRC3 results in nonspecific post-transcriptional inhibition of LRAs. Conclusion: LRAs are not a reliable technique to assess the inhibitory function of NLRs. Downloaded from Significance: The inhibitory role of NLRs on specific signal transduction pathways needs to be reevaluated. Luciferase reporter assays (LRAs) are widely used to assess the Nod-like receptors (NLRs)7 represent an important class of activity of specific signal transduction pathways. Although pow- intracellular pattern recognition molecules (PRMs), which are erful, rapid and convenient, this technique can also generate implicated in the detection and response to microbe- and dan- www.jbc.org artifactual results, as revealed for instance in the case of high ger-associated molecular patterns (MAMPs and DAMPs), throughput screens of inhibitory molecules.
    [Show full text]
  • ATP-Binding and Hydrolysis in Inflammasome Activation
    molecules Review ATP-Binding and Hydrolysis in Inflammasome Activation Christina F. Sandall, Bjoern K. Ziehr and Justin A. MacDonald * Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada; [email protected] (C.F.S.); [email protected] (B.K.Z.) * Correspondence: [email protected]; Tel.: +1-403-210-8433 Academic Editor: Massimo Bertinaria Received: 15 September 2020; Accepted: 3 October 2020; Published: 7 October 2020 Abstract: The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As members of the STAND ATPases, the NLRs are generally thought to share a similar model of ATP-dependent activation and effect. However, recent observations have challenged this paradigm to reveal novel and complex biochemical processes to discern NLRs from other STAND proteins. In this review, we highlight past findings that identify the regulatory importance of conserved ATP-binding and hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explore recent breakthroughs that generate connections between NLR protein structure and function. Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectives on the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations of NLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctions in nucleotide-binding domain topology with occupancy of ATP or ADP that are in turn disseminated on to the global protein structure.
    [Show full text]
  • Blau Syndrome Polymorphisms in NOD2 Identify Nucleotide Hydrolysis and Helical Domain 1 As Signalling Regulators ⇑ Rhiannon Parkhouse A, Joseph P
    FEBS Letters 588 (2014) 3382–3389 journal homepage: www.FEBSLetters.org Blau syndrome polymorphisms in NOD2 identify nucleotide hydrolysis and helical domain 1 as signalling regulators ⇑ Rhiannon Parkhouse a, Joseph P. Boyle a,b, Tom P. Monie a,b, a Department of Biochemistry, University of Cambridge, Cambridge, UK b Department of Veterinary Medicine, University of Cambridge, Cambridge, UK article info abstract Article history: Understanding how single nucleotide polymorphisms (SNPs) lead to disease at a molecular level Received 10 June 2014 provides a starting point for improved therapeutic intervention. SNPs in the innate immune recep- Revised 23 July 2014 tor nucleotide oligomerisation domain 2 (NOD2) can cause the inflammatory disorders Blau Syn- Accepted 23 July 2014 drome (BS) and early onset sarcoidosis (EOS) through receptor hyperactivation. Here, we show Available online 2 August 2014 that these polymorphisms cluster into two primary locations: the ATP/Mg2+-binding site and helical Edited by Renee Tsolis domain 1. Polymorphisms in these two locations may consequently dysregulate ATP hydrolysis and NOD2 autoinhibition, respectively. Complementary mutations in NOD1 did not mirror the NOD2 phenotype, which indicates that NOD1 and NOD2 are activated and regulated by distinct methods. Keywords: Nucleotide-binding, leucine-rich repeat Ó 2014 The Authors. Published by Elsevier B.V. on behalf of the Federation of European Biochemical containing receptor Societies. This is an open access article under the CC BY license (http://creativecommons.org/licenses/
    [Show full text]
  • Mesenchymal Stromal Cells Inhibit NLRP3 Inflammasome Activation In
    www.nature.com/scientificreports OPEN Mesenchymal stromal cells inhibit NLRP3 infammasome activation in a model of Coxsackievirus Received: 21 February 2017 Accepted: 16 January 2018 B3-induced infammatory Published: xx xx xxxx cardiomyopathy Kapka Miteva1,2, Kathleen Pappritz1,2, Marzena Sosnowski1, Muhammad El-Shafeey1,3, Irene Müller1,2, Fengquan Dong1, Konstantinos Savvatis1, Jochen Ringe1,4, Carsten Tschöpe1,2,5 & Sophie Van Linthout1,2,5 Infammation in myocarditis induces cardiac injury and triggers disease progression to heart failure. NLRP3 infammasome activation is a newly identifed amplifying step in the pathogenesis of myocarditis. We previously have demonstrated that mesenchymal stromal cells (MSC) are cardioprotective in Coxsackievirus B3 (CVB3)-induced myocarditis. In this study, MSC markedly inhibited left ventricular (LV) NOD2, NLRP3, ASC, caspase-1, IL-1β, and IL-18 mRNA expression in CVB3-infected mice. ASC protein expression, essential for NLRP3 infammasome assembly, increased upon CVB3 infection and was abrogated in MSC-treated mice. Concomitantly, CVB3 infection in vitro induced NOD2 expression, NLRP3 infammasome activation and IL-1β secretion in HL-1 cells, which was abolished after MSC supplementation. The inhibitory efect of MSC on NLRP3 infammasome activity in HL-1 cells was partly mediated via secretion of the anti-oxidative protein stanniocalcin-1. Furthermore, MSC application in CVB3-infected mice reduced the percentage of NOD2-, ASC-, p10- and/or IL-1β-positive splenic macrophages, natural killer cells, and dendritic cells. The suppressive efect of MSC on infammasome activation was associated with normalized expression of prominent regulators of myocardial contractility and fbrosis to levels comparable to control mice. In conclusion, MSC treatment in myocarditis could be a promising strategy limiting the adverse consequences of cardiac and systemic NLRP3 infammasome activation.
    [Show full text]
  • A Role for the Pattern Recognition Receptor Nod2 in Promoting Recruitment of CD103&Plus; Dendritic Cells to the Colon In
    ARTICLES nature publishing group A role for the pattern recognition receptor Nod2 in promoting recruitment of CD103 þ dendritic cells to the colon in response to Trichuris muris infection R Bowcutt1,4, M Bramhall1, L Logunova1, J Wilson2, C Booth2, SR Carding3, R Grencis1 and S Cruickshank1 The ability of the colon to generate an immune response to pathogens, such as the model pathogen Trichuris muris,isa fundamental and critical defense mechanism. Resistance to T. muris infection is associated with the rapid recruitment of dendritic cells (DCs) to the colonic epithelium via epithelial chemokine production. However, the epithelial–pathogen interactions that drive chemokine production are not known. We addressed the role of the cytosolic pattern recognition receptor Nod2. In response to infection, there was a rapid influx of CD103 þ CD11c þ DCs into the colonic epithelium in wild-type (WT) mice, whereas this was absent in Nod2 À / À animals. In vitro chemotaxis assays and in vivo experiments using bone marrow chimeras of WT mice reconstituted with Nod2 À / À bone marrow and infected with T. muris demonstrated that the migratory function of Nod2 À / À DCs was normal. Investigation of colonic epithelial cell (CEC) innate responses revealed a significant reduction in epithelial production of the chemokines CCL2 and CCL5 but not CCL20 by Nod2-deficient CECs. Collectively, these data demonstrate the importance of Nod2 in CEC responses to infection and the requirement for functional Nod2 in initiating host epithelial chemokine-mediated responses and subsequent DC recruitment and T-cell responses following infection. INTRODUCTION characterized, how and why these immune responses are The gastrointestinal-dwelling parasite, Trichuris muris initiated is still unclear.
    [Show full text]
  • The Bacterial Peptidoglycan-Sensing Molecules NOD1 and NOD2 Promote CD8 + Thymocyte Selection
    The Bacterial Peptidoglycan-Sensing Molecules NOD1 and NOD2 Promote CD8 + Thymocyte Selection This information is current as Marianne M. Martinic, Irina Caminschi, Meredith O'Keeffe, of September 24, 2021. Therese C. Thinnes, Raelene Grumont, Steve Gerondakis, Dianne B. McKay, David Nemazee and Amanda L. Gavin J Immunol published online 15 February 2017 http://www.jimmunol.org/content/early/2017/02/15/jimmun ol.1601462 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/02/15/jimmunol.160146 Material 2.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 15, 2017, doi:10.4049/jimmunol.1601462 The Journal of Immunology The Bacterial Peptidoglycan-Sensing Molecules NOD1 and NOD2 Promote CD8+ Thymocyte Selection Marianne M. Martinic,*,1 Irina Caminschi,†,‡,2 Meredith O’Keeffe,†,2 Therese C. Thinnes,* Raelene Grumont,†,2 Steve Gerondakis,†,2 Dianne B.
    [Show full text]
  • NOD2: Activation During Bacterial and Viral Infections, Polymorphisms
    REVISTA DE INVESTIGACIÓN CLÍNICA Contents available at PubMed www.clinicalandtranslationalinvestigation.com PERMANYER Rev Inves Clin. 2018;70:18-28 IN-DEPTH REVIEW NOD2: Activation During Bacterial and Viral Infections, Polymorphisms and Potential as Therapeutic Target Diana Alhelí Domínguez-Martínez1, Daniel Núñez-Avellaneda1, Carlos Alberto Castañón-Sánchez2 and Ma Isabel Salazar3* 1Laboratorio de Inmunología Celular e Inmunopatogénesis, Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City; 2Subdirección de Enseñanza e Investigación, Hospital Regional de Alta Especialidad de Oaxaca, San Bartolo Coyotepec, Oax.; 3Sección de Inmunovirología, Laboratorio de Virología, Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico ABSTRACT Nucleotide-binding domain (NBD) leucine-rich repeat (LRR)-containing receptors or NLRs are a family of receptors that detect both, molecules associated to pathogens and alarmins, and are located mainly in the cytoplasm. NOD2 belongs to the NLR family and is a dynamic receptor capable of interacting with multiple proteins and modulate immune responses in a stimuli-dependent manner. The experimental evidence shows that interaction between NOD2 structural domains and the effector proteins shape the overall response against bacterial or viral infections. Other reports have focused on the importance of NOD2 not only in infection but also in maintaining tissue homeostasis. However, not only protein interactions relate to function but also certain polymorphisms in the gene that encodes NOD2 have been associated with inflammatory diseases, such as Crohn’s disease. Here, we review the importance and general characteristics of NOD2, discussing its participation in infections caused by bacteria and viruses as well as its interaction with other pathogen recognition receptors or effectors to induce antibacterial and antiviral responses.
    [Show full text]
  • Rnai Screening Identifies Mediators of NOD2 Signaling
    RNAi screening identifies mediators of NOD2 signaling: Implications for spatial specificity of MDP recognition Simone Lipinskia,1, Nils Grabea,1, Gunnar Jacobsa, Susanne Billmann-Borna, Andreas Tilla,b, Robert Häslera, Konrad Adena, Maren Paulsena, Alexander Arltc, Lars Kraemera, Nina Hagemannd, Kai Sven Erdmannd, Stefan Schreibera,c,2, and Philip Rosenstiela,2,3 aInstitute of Clinical Molecular Biology, Christian Albrechts University, D-24105 Kiel, Germany; bSection of Molecular Biology, Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093-0130; cDepartment of General Internal Medicine, University Hospital Schleswig-Holstein, D-24105 Kiel, Germany; and dDepartment of Biochemistry II, Ruhr University Bochum, D-44780 Bochum, Germany Edited by Jenny P.-Y. Ting, University of North Carolina, Chapel Hill, NC, and accepted by the Editorial Board October 26, 2012 (received for review June 7, 2012) The intracellular nucleotide-binding oligomerization domain-2 mechanism has been proposed so far. To identify modulators of (NOD2) receptor detects bacteria-derived muramyl dipeptide NOD2 signaling, we performed a high-throughput siRNA screen (MDP) and activates the transcription factor NF-κB. Here we de- targeting 7,783 genes. Among the genes identified was FRMPD2 scribe the regulatome of NOD2 signaling using a systematic RNAi (FERM and PDZ domain protein-containing 2), a protein in- screen. Using three consecutive screens, we identified a set of 20 volved in basolateral membrane targeting in epithelial cells (20). fi positive NF-κB regulators including the known pathway members We show here that FRMPD2 supports basolateral speci city of RIPK2, RELA, and BIRC4 (XIAP) as well as FRMPD2 (FERM and PDZ MDP recognition by NOD2 in polarized intestinal epithelial cells domain-containing 2).
    [Show full text]
  • Structural Models of Zebrafish (Danio Rerio) NOD1 and NOD2 NACHT
    RESEARCH ARTICLE Structural Models of Zebrafish (Danio rerio) NOD1 and NOD2 NACHT Domains Suggest Differential ATP Binding Orientations: Insights from Computational Modeling, Docking and Molecular Dynamics Simulations Jitendra Maharana1,2*, Bikash Ranjan Sahoo1, Aritra Bej1, Itishree Jena1☯, Arunima Parida1☯, Jyoti Ranjan Sahoo1, Budheswar Dehury3, Mahesh Chandra Patra1, Sushma Rani Martha1, Sucharita Balabantray1, Sukanta Kumar Pradhan1, Bijay Kumar Behera2* 1 Department of Bioinformatics, Orissa University of Agriculture and Technology,Bhubaneswar, Odisha, India, 2 Biotechnology Laboratory, ICAR-Central Inland Fisheries Research Institute, Barrackpore, Kolkata, West Bengal, India, 3 Biomedical Informatics Centre, Regional Medical Research Institute (ICMR), Bhubaneswar, Odisha, India OPEN ACCESS ☯ These authors contributed equally to this work. Citation: Maharana J, Sahoo BR, Bej A, Jena I, * [email protected] (JM); mailto: [email protected] (BKB) Parida A, Sahoo JR, et al. (2015) Structural Models of Zebrafish (Danio rerio) NOD1 and NOD2 NACHT Domains Suggest Differential ATP Binding Orientations: Insights from Computational Modeling, Abstract Docking and Molecular Dynamics Simulations. PLoS ONE 10(3): e0121415. doi:10.1371/journal. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and NOD2 are cy- pone.0121415 tosolic pattern recognition receptors playing pivotal roles in innate immune signaling. NOD1 Academic Editor: Ivo G. Boneca, Institut Pasteur and NOD2 recognize bacterial peptidoglycan derivatives iE-DAP and MDP, respectively Paris, FRANCE and undergoes conformational alternation and ATP-dependent self-oligomerization of Received: September 23, 2014 NACHT domain followed by downstream signaling. Lack of structural adequacy of NACHT Accepted: February 1, 2015 domain confines our understanding about the NOD-mediated signaling mechanism. Here, we predicted the structure of NACHT domain of both NOD1 and NOD2 from model organ- Published: March 26, 2015 ism zebrafish (Danio rerio) using computational methods.
    [Show full text]