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Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin.

ABSTRACT: Tracheal cytotoxin (TCT) was originally described as the minimal effector that was able to reproduce the cytotoxic response of Bordetella pertussis on ciliated epithelial cells. This molecule triggers pleiotropic effects such as immune stimulation or slow-wave sleep modulation. Further characterization identified TCT as a specific diaminopimelic acid (DAP)-containing muropeptide, GlcNAc-(anhydro)MurNAc-L-Ala-D-Glu-mesoDAP-D-Ala. Here, we show that the biological activity of TCT depends on Nod1, an intracellular sensor of bacterial peptidoglycan. However, Nod1-dependent detection of TCT was found to be host specific, as human Nod1 (hNod1) poorly detected TCT, whereas mouse Nod1 (mNod1) did so efficiently. More generally, hNod1 required a tripeptide (L-Ala-D-Glu-mesoDAP) for efficient sensing of peptidoglycan, whereas mNod1 detected a tetrapeptide structure (L-Ala-D-Glu-mesoDAP-D-Ala). In murine macrophages, TCT stimulated cytokine secretion and NO production through Nod1. Finally, in vivo, injection of the tetrapeptide structure in mice triggered a transient yet strong release of cytokines into the bloodstream and the maturation of macrophages, in a Nod1-dependent manner. This study thereby identifies Nod1 as the long sought after sensor of TCT in mammals.

SUBMITTER: Magalhaes JG

PROVIDER: S-EPMC1369207 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin.

Magalhaes Joao Gamelas JG Philpott Dana J DJ Nahori Marie-Anne MA Jéhanno Muguette M Fritz Joerg J Le Bourhis Lionel L Viala Jérôme J Hugot Jean-Pierre JP Giovannini Marco M Bertin John J Lepoivre Michel M Mengin-Lecreulx Dominique D Sansonetti Philippe J PJ Girardin Stephen E SE

EMBO reports 20051201 12

Tracheal cytotoxin (TCT) was originally described as the minimal effector that was able to reproduce the cytotoxic response of Bordetella pertussis on ciliated epithelial cells. This molecule triggers pleiotropic effects such as immune stimulation or slow-wave sleep modulation. Further characterization identified TCT as a specific diaminopimelic acid (DAP)-containing muropeptide, GlcNAc-(anhydro)MurNAc-L-Ala-D-Glu-mesoDAP-D-Ala. Here, we show that the biological activity of TCT depends on Nod1, ...[more]

PMID: 16211083

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Project description:ObjectiveInsulin resistance associates with chronic inflammation, and participatory elements of the immune system are emerging. We hypothesized that bacterial elements acting on distinct intracellular pattern recognition receptors of the innate immune system, such as bacterial peptidoglycan (PGN) acting on nucleotide oligomerization domain (NOD) proteins, contribute to insulin resistance.Research design and methodsMetabolic and inflammatory properties were assessed in wild-type (WT) and NOD1/2(-/-) double knockout mice fed a high-fat diet (HFD) for 16 weeks. Insulin resistance was measured by hyperinsulinemic euglycemic clamps in mice injected with mimetics of meso-diaminopimelic acid-containing PGN or the minimal bioactive PGN motif, which activate NOD1 and NOD2, respectively. Systemic and tissue-specific inflammation was assessed using enzyme-linked immunosorbent assays in NOD ligand-injected mice. Cytokine secretion, glucose uptake, and insulin signaling were assessed in adipocytes and primary hepatocytes exposed to NOD ligands in vitro.ResultsNOD1/2(-/-) mice were protected from HFD-induced inflammation, lipid accumulation, and peripheral insulin intolerance. Conversely, direct activation of NOD1 protein caused insulin resistance. NOD1 ligands induced peripheral and hepatic insulin resistance within 6 h in WT, but not NOD1(-/-), mice. NOD2 ligands only modestly reduced peripheral glucose disposal. NOD1 ligand elicited minor changes in circulating proinflammatory mediators, yet caused adipose tissue inflammation and insulin resistance of muscle AS160 and liver FOXO1. Ex vivo, NOD1 ligand caused proinflammatory cytokine secretion and impaired insulin-stimulated glucose uptake directly in adipocytes. NOD1 ligand also caused inflammation and insulin resistance directly in primary hepatocytes from WT, but not NOD1(-/-), mice.ConclusionsWe identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. Acute activation of NOD proteins by mimetics of bacterial PGNs causes whole-body insulin resistance, bolstering the concept that innate immune responses to distinctive bacterial cues directly lead to insulin resistance. Hence, NOD1 is a plausible, new link between innate immunity and metabolism.

Dataset Information

Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin.

Publications

Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin.

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