New Role of Nod Proteins in Regulation of Intestinal Goblet Cell Response in the Context of Innate Host Defense in an Enteric Parasite Infection

Wang, Huaqing; Kim, Janice J.; Denou, Emmanuel; Gallagher, Amanda; Thornton, David J.; Shajib, Md. Sharif; Xia, Lijun; Schertzer, Jonathan D.; Grencis, Richard K.; Philpott, Dana J.; Khan, Waliul I.

doi:10.1128/iai.01187-15

Cited by 30 publications

(27 citation statements)

References 42 publications

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“…Nod1 and Nod2 ligands have been found to play important roles in modulating a range of host physiological responses in the mutually beneficial interactions between microbe and host, including inducing lymphoid tissue genesis, 50 maintaining Goblet cells, 51,52 promoting mucosal adjuvant activity of cholera toxin, 53 and inducing expression of hematopoietic cytokines by mesenchymal stromal cells to promote hematopoiesis. 44 How the Nod1 and Nod2 ligands are liberated from the bacterial wall was previously unknown.…”

Section: Discussionmentioning

confidence: 99%

Intestinal lysozyme liberates Nod1 ligands from microbes to direct insulin trafficking in pancreatic beta cells

et al. 2019

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Long-range communication between intestinal symbiotic bacteria and extra-intestinal organs can occur through circulating bacterial signal molecules, through neural circuits, or through cytokines or hormones from host cells. Here we report that Nod1 ligands derived from intestinal bacteria act as signal molecules and directly modulate insulin trafficking in pancreatic beta cells. The cytosolic peptidoglycan receptor Nod1 and its downstream adapter Rip2 are required for insulin trafficking in beta cells in a cellautonomous manner. Mechanistically, upon recognizing cognate ligands, Nod1 and Rip2 localize to insulin vesicles, recruiting Rab1a to direct insulin trafficking through the cytoplasm. Importantly, intestinal lysozyme liberates Nod1 ligands into the circulation, thus enabling long-range communication between intestinal microbes and islets. The intestine-islet crosstalk bridged by Nod1 ligands modulates host glucose tolerance. Our study defines a new type of inter-organ communication based on circulating bacterial signal molecules, which has broad implications for understanding the mutualistic relationship between microbes and host.

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Section: Discussionmentioning

confidence: 99%

Intestinal lysozyme liberates Nod1 ligands from microbes to direct insulin trafficking in pancreatic beta cells

et al. 2019

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“…speculated that NOD2 ligands are expressed on the worm itself. While the T. muris studies3860 have shown that NOD2 activation does not always rely on the presence of MDP, future studies should investigate which nematode-derived molecules from Wolbachia -free species activate NOD2 signaling. Studies with filarial infected humans have not focused on the NOD2 receptor so far.…”

Section: Discussionmentioning

confidence: 99%

“…They demonstrated a significantly delayed parasite expulsion in the intestine of these mice. Their data provides evidence that NOD proteins are triggering goblet cell responses and mucus production in the context of enteric T. muris infection60. However, in contrast to the filarial nematode L. sigmodontis, T. muris does not harbor intracellular bacteria, e.g.…”

Section: Discussionmentioning

confidence: 99%

NOD2 dependent neutrophil recruitment is required for early protective immune responses against infectious Litomosoides sigmodontis L3 larvae

Ajendra

Specht

Ziewer

et al. 2016

Sci Rep

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Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) recognizes muramyl dipeptide (MDP) of bacterial cell walls, triggering NFκB-induced pro-inflammation. As most human pathogenic filariae contain Wolbachia endobacteria that synthesize the MDP-containing cell wall precursor lipid II, NOD2’s role during infection with the rodent filaria Litomosoides sigmodontis was investigated. In NFκB reporter-cells, worm-extract containing Wolbachia induced NOD2 and NOD1. NOD2-deficient mice infected with L. sigmodontis had significantly more worms than wildtype controls early in infection. Increased worm burden was not observed after subcutaneous infection, suggesting that protective NOD2-dependent immune responses occur within the skin. Flow cytometry demonstrated that neutrophil recruitment to the skin was impaired in NOD2−/− mice after intradermal injection of third stage larvae (L3), and blood neutrophil numbers were reduced after L. sigmodontis infection. PCR array supported the requirement of NOD2 for recruitment of neutrophils to the skin, as genes associated with neutrophil recruitment and activation were downregulated in NOD2−/− mice after intradermal L3 injection. Neutrophil depletion before L. sigmodontis infection increased worm recovery in wildtype mice, confirming that neutrophils are essential against invading L3 larvae. This study indicates that NOD-like receptors are implemented in first-line protective immune responses against filarial nematodes.

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“…Another possible defence mechanism of the mucus is the physical barrier itself, which interferes in nematode feeding and mobility. This would explain why nematode infections induce a hyperplasia of the goblet cells in the host 31 . According to our results, the group of infected mice pre-treated with the anti-IL-23 antibody had the highest (***) quantity of mucus in the crypts and reduced nematode load, whereas the rest of the groups, AB-C, C and C-IF, presented lower mucus production.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study investigating the role played by the intracellular “Nod receptor” in goblet cell activation during the process of inflammation and its effect on the expulsion of Trichuris muris 31 showed that the activation of mucus-producing goblet cells is mediated by the binomial response of the IL-25- IL-9 -IL-13 29 , 32 – 34 . IL-13 is the regulator of goblet cell hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

Intraperitoneal administration of the anti-IL-23 antibody prevents the establishment of intestinal nematodes in mice

Samblas

Bernal

Bolado-Ortiz

et al. 2018

Sci Rep

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Previous studies have established that an increased Th-9 response creates a hostile environment for nematode parasites. Given that IL-23, a cytokine required for maintenance of the IL-17–secreting phenotype, has inhibitory effects on IL-9 production, we hypothesized that reducing circulating IL-23 by treatment with anti-IL-23 antibodies would reduce the establishment and development of parasitic intestinal nematodes. In this study, we show that animals treated with anti-IL-23 monoclonal antibodies showed a drastic reduction in the number of mouse pinworms (Aspiculuris tetraptera) recovered from the intestine (p < 0.001) at 23 days post-infection compared to the untreated animals. The cytokine levels in Peyer’s patches (PP) in treated and infected animals increase the expression of interleukins such as IL-25, IL-21, and IL-9, augmenting mucus production in the crypts, and boosting chemokines, such as OX40 and CCL20 in the mucosa. Our results suggest that the Th17/Th2 regulatory mechanism provoked by the administration of the anti-IL-23 antibody prevents the implantation of the intestinal nematode in mice. The diminished inflammatory IL-17 levels alter the Th9 environment perhaps as a consequence of IL-17 inhibiting IL-9 expression. These Th9 conditions may explain the successful treatment against Inflammatory Bowel Disease (IBD) both with antibodies against IL-23 or through parasitization with nematodes.

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New Role of Nod Proteins in Regulation of Intestinal Goblet Cell Response in the Context of Innate Host Defense in an Enteric Parasite Infection

Cited by 30 publications

References 42 publications

Intestinal lysozyme liberates Nod1 ligands from microbes to direct insulin trafficking in pancreatic beta cells

Intestinal lysozyme liberates Nod1 ligands from microbes to direct insulin trafficking in pancreatic beta cells

NOD2 dependent neutrophil recruitment is required for early protective immune responses against infectious Litomosoides sigmodontis L3 larvae

Intraperitoneal administration of the anti-IL-23 antibody prevents the establishment of intestinal nematodes in mice

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