How the Intricate Interaction among Toll-Like Receptors, Microbiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology

Frosali, Simona; Pagliari, Danilo; Gambassi, Giovanni; Landolfi, Raffaele; Pandolfi, Franco; Cianci, Rossella

doi:10.1155/2015/489821

Cited by 207 publications

(195 citation statements)

References 106 publications

(129 reference statements)

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“…Various mechanisms have been described through which the intestinal microbiota may interact with mucosal immunity (Hooper et al, 2012;El Aidy et al, 2015). One key pathway is tolllike receptor (TLR) signalling, which can influence regulatory T-cell populations, the autophagy pathway (Sun et al, 2011;Frosali et al, 2015), cellular epithelial proliferation, cytoprotective effects, immune cell recruitment, IgA production and secretion of antimicrobial peptides (RakoffNahoum et al, 2004;Shang et al, 2008;El Aidy et al, 2015). It is also increasingly evident that enteric bacteria influence production of effector CD4+ T helper (Th) cells, which are imperative in protecting the gut from developing colitis (Kullberg et al, 2002;Kamada & Núñez, 2014).…”

Section: Microbiota-immune System Cross-talkmentioning

confidence: 99%

“…Bacteria can activate both the innate (macrophage, neutrophil and dendritic cells) and acquired (T and B cell) immune systems (Sartor, 2006;Hooper et al, 2012;Alexander et al, 2014;Kayama & Takeda, 2016). Bacteria can act as adjuvants to activated innate immune cells or as antigens to stimulate clonal expansion of T cells (Sartor, 2007;Frosali et al, 2015;Tanoue et al, 2016 (Zareie et al, 2001;Mahida, 2000;de Zoeten & Fuss, 2013). High levels of these pro-inflammatory molecules promote trafficking and migration of the circulating immune effector cells to the intestinal mucosa (Reaves et al, 2005;Griffith et al, 2014;Peterson & Artis, 2014).…”

Section: Dysbiosis and The Dysregulated Immune Responsementioning

confidence: 99%

“…NOD2 is primarily involved in bacterial clearance though binding muramyl dipeptide (MDP) to produce a number of antimicrobial peptides including defensins and mediates immune responses through activation of NFkB (Hruz et al, 2009;Dickson, 2016). Mutant CARD15 was found to be associated with defective clearance of invasive bacteria, accumulation of luminal and mucosal enteric flora and an exaggerated immune response owing to over-activation of NFkB (Sartor, 2006;Frosali et al, 2015). CARD15 mutants including Arg702Trp, Gly908Arg and Leu1007 fsins C were found at higher rates in families affected with CD and are associated with a 2-4-fold relative risk increase of CD in heterozygous individuals and to 20-40-fold Hold et al (2014) relative risk increase in homozygous individuals (Li et al, 2004;Cuthbert et al, 2002).…”

Section: Card15/nod2 Genementioning

confidence: 99%

See 2 more Smart Citations

An overview of the bacterial contribution to Crohn disease pathogenesis

Alhagamhmad

Day

Lemberg

et al. 2016

Journal of Medical Microbiology

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Section: Microbiota-immune System Cross-talkmentioning

confidence: 99%

Section: Dysbiosis and The Dysregulated Immune Responsementioning

confidence: 99%

Section: Card15/nod2 Genementioning

confidence: 99%

See 1 more Smart Citation

An overview of the bacterial contribution to Crohn disease pathogenesis

Alhagamhmad

Day

Lemberg

et al. 2016

Journal of Medical Microbiology

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“…4 Several regulatory mechanisms that control TLR activation have been described, thus preventing excessive inflammatory responses to the resident microbiota. 5 In particular, many host-derived and environment metabolites can influence immune reactivity and TLR activation, with significant effects on mucosal immune homeostasis. 6 Coordination between Supplemental digital content is available for this article.…”

mentioning

confidence: 99%

Histamine Receptor 2 is Required to Suppress Innate Immune Responses to Bacterial Ligands in Patients with Inflammatory Bowel Disease

Smolińska

Groeger

Pérez

et al. 2016

Inflammatory Bowel Diseases

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BACKGROUND: Histamine is a key immunoregulatory mediator in immediate-type hypersensitivity reactions and chronic inflammatory responses, in particular histamine suppresses proinflammatory responses to bacterial ligands, through histamine receptor 2 (H2R). The aim of this study was to investigate the effects of histamine and H2R on bacteria-induced inflammatory responses in patients with IBD. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with Crohn's disease, patients with ulcerative colitis, and healthy controls. PBMC histamine receptor expression was evaluated by flow cytometry. Cytokine secretion following Toll-like receptor (TLR)-2, TLR-4, TLR-5, or TLR-9 stimulation in the presence or absence of histamine or famotidine (H2R antagonist) was quantified. Biopsy histamine receptor gene expression was evaluated using reverse transcription-polymerase chain reaction. The in vivo role of H2R was evaluated in the T-cell transfer murine colitis model. RESULTS: The percentage of circulating H2R monocytes was significantly reduced in patients with IBD. Histamine effectively suppressed TLR-induced cytokine secretion from healthy volunteer PBMCs but not for PBMCs from patients with IBD. Famotidine reversed this suppressive effect. H1R, H2R, and H4R gene expression was increased in inflamed gastrointestinal mucosa compared with noninflamed mucosa from the same patient and expression levels correlated with proinflammatory cytokine gene expression. Mice receiving lymphocytes from H2R donors, or treated with famotidine, displayed more severe weight loss, higher disease scores and increased numbers of mucosal IFN-and IL-17 T cells. CONCLUSION: Patients with IBD display dysregulated expression of histamine receptors, with diminished anti-inflammatory effects associated with H2R signaling. Deliberate manipulation of H2R signaling may suppress excessive TLR responses to bacteria within the gut.

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“…PRRs are expressed in intestinal epithelial cells [11,12] and are able to recognize microbial-associated molecular patterns (MAMPs) to develop either inflammatory or tolerance responses [13]. In this context, several studies have reported that numerous PRRs, as TLR2, TLR4 [14] and NOD2 [15], seem to be implicated in IBD due to the dysfunctional recognition of commensal microbiota [16]. TLR2 is expressed in the cell surface and can detect molecular patterns associated with Gram-positive bacteria [17] through their heterodimers (TLR2/1 and TLR2/6) [18] while TLR4, also located on the cell surface, detects lipopolysaccharide (LPS), the major cell wall component of Gramnegative bacteria [19].…”

Section: Introductionmentioning

confidence: 99%

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

Layunta

Latorre

Forcén

et al. 2018

Cell Physiol Biochem

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Background/Aims: Serotonin (5-HT) is a chief modulator of intestinal activity. The effects of 5-HT depend on its extracellular availability, which is mainly controlled by serotonin transporter (SERT), expressed in enterocytes. On the other hand, innate immunity, mediated by Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), is known to control intestinal microbiota and maintain intestinal homeostasis. The dysregulation of the intestinal serotonergic system and innate immunity has been observed in inflammatory bowel diseases (IBD), the incidence of which has severely increased all over the world. The aim of the present study, therefore, was to analyze the effect of NOD2 on intestinal SERT activity and expression, as well as to study the crosstalk of NOD2 with TLR2 and TLR4. Methods: Intestinal epithelial cell line Caco-2/TC7 was used to analyze SERT activity and SERT, NOD2, TLR2 and TLR4 molecular expression by real-time PCR and western blotting. Moreover, intestinal tract (ileum and colon) from mice deficient in TLR2, TLR4 or TLR2/4 receptors was used to test the interdependence of NOD2 with these TLR receptors. Results: NOD2 activation inhibits SERT activity in Caco-2/TC7 cells, mainly due to the decrement of SERT molecular expression, with RIP2/RICK being the intracellular pathway involved in this effect. This inhibitory effect on SERT would yield an increment of extracellular 5-HT availability. In this sense, 5-HT strongly inhibits NOD2 expression. In addition, NOD2 showed greater interdependence with TLR2 than with TLR4. Indeed, NOD2 expression significantly increased in both cells treated with TLR2 agonists and the intestinal tract of Tlr2-/- mice. Conclusions: It may be inferred from our data that NOD2 could play a role in intestinal pathophysiology not only through its inherent innate immune role but also due to its interaction with other receptors as TLR2 and the modulation of the intestinal serotonergic system decreasing SERT activity and expression.

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How the Intricate Interaction among Toll-Like Receptors, Microbiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology

Cited by 207 publications

References 106 publications

An overview of the bacterial contribution to Crohn disease pathogenesis

An overview of the bacterial contribution to Crohn disease pathogenesis

Histamine Receptor 2 is Required to Suppress Innate Immune Responses to Bacterial Ligands in Patients with Inflammatory Bowel Disease

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

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