Dataset Information

P204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling in Mice.

ABSTRACT: p204, a murine member of an interferon-inducible p200 family, was reported to recognize intracellular viral and bacterial DNAs, however, its role in the innate immunity in vivo remains unknown due to the lack of p204-deficient animal models. In this study we first generated the p204^-/- mice. Unexpectedly, p204 deficiency led to significant defect in extracellular LPS signaling in macrophages, as demonstrated by dramatic reductions of LPS-mediated IFN-? and pro-inflammatory cytokines. The serum levels of IFN-? and pro-inflammatory cytokines were also significantly reduced in p204^-/- mice following LPS challenge. In addition, p204^-/- mice were resistant to LPS-induced shock. LPS-activated NF-?B and IRF-3 pathways were all defective in p204-deficient macrophages. p204 binds to TLR4 through its Pyrin domain, and it is required for the dimerization of TLR4 following LPS-challenge. Collectively, p204 is a critical component of canonical LPS-TLR4 signaling pathway, and these studies also suggest that p204 could be a potential target to prevent and treat inflammatory and infectious diseases.

SUBMITTER: Yi YS

PROVIDER: S-EPMC5925582 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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p204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling in Mice.

Yi Young-Su YS Jian Jinlong J Gonzalez-Gugel Elena E Shi Yong-Xiang YX Tian Qingyun Q Fu Wenyu W Hettinghouse Aubryanna A Song Wenhao W Liu Ronghan R He Michun M Qi Huabing H Yang Jing J Du Xiaolan X Xiao GuoZhi G Chen Lin L Liu Chuan-Ju CJ

EBioMedicine 20180216

p204, a murine member of an interferon-inducible p200 family, was reported to recognize intracellular viral and bacterial DNAs, however, its role in the innate immunity in vivo remains unknown due to the lack of p204-deficient animal models. In this study we first generated the p204<sup>-/-</sup> mice. Unexpectedly, p204 deficiency led to significant defect in extracellular LPS signaling in macrophages, as demonstrated by dramatic reductions of LPS-mediated IFN-β and pro-inflammatory cytokines. ...[more]

PMID: 29472103

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Project description:Acute lung injury (ALI) with uncontrolled inflammatory response has high morbidity and mortality rates in critically ill patients. Pathogen-associated molecular patterns (PAMPs) are involved in the development of uncontrolled inflammatory response injury and associated lethality. In this study, we investigated the inhibit effect of MS19, a microsatellite DNA-derived oligodeoxynucleotide (ODN) with AAAG repeats, on the inflammatory response induced by various PAMPs in vitro and in vivo. In parallel, a microsatellite DNA with AAAC repeats, named as MS19-C, was used as controls. We found that MS19 extensively inhibited the expression of inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α induced by various PAMPs stimulation, including DNA viruses, RNA viruses, bacterial components lipopolysaccharide (LPS), and curdlan, as well as the dsDNA and dsRNA mimics, in primed bone marrow-derived macrophage (BMDM). Other than various PAMPs, MS19 also demonstrated obvious effects on blocking the high mobility group box1 (HMGB1), a representative damage-associated-molecular pattern (DAMP), nuclear translocation and secretion. With the base substitution from G to C, MS19-C has been proved that it has lost the inhibitory effect. The inhibition is associated with nuclear factor kappa B (NF-κB) signaling but not the mitogen-activated protein kinase (MAPK) transduction. Moreover, MS19 capable of inhibiting the IL-6 and TNF-α production and blocking the HMGB1 nuclear translocation and secretion in LPS-stimulated cells was used to treat mice ALI induced by LPS in vivo. In the ALI mice model, MS19 significantly inhibited the weight loss and displayed the dramatic effect on lessening the ALI by reducing consolidation, hemorrhage, intra-alveolar edema in lungs of the mice. Meanwhile, MS19 could increase the survival rate of ALI by downregulating the inflammation cytokines HMGB1, TNF-a, and IL-6 production in the bronchoalveolar lavage fluid (BALF). The data suggest that MS19 might display its therapeutic role on ALI by inhibiting the HMGB1-TLR4-NF-κB signaling pathway.

Project description:BackgroundParkinson's disease (PD) is a prevalent neurodegenerative disorder, displaying not only well-known motor deficits but also gastrointestinal dysfunctions. Consistently, it has been increasingly evident that gut microbiota affects the communication between the gut and the brain in PD pathogenesis, known as the microbiota-gut-brain axis. As an approach to re-establishing a normal microbiota community, fecal microbiota transplantation (FMT) has exerted beneficial effects on PD in recent studies. Here, in this study, we established a chronic rotenone-induced PD mouse model to evaluate the protective effects of FMT treatment on PD and to explore the underlying mechanisms, which also proves the involvement of gut microbiota dysbiosis in PD pathogenesis via the microbiota-gut-brain axis.ResultsWe demonstrated that gut microbiota dysbiosis induced by rotenone administration caused gastrointestinal function impairment and poor behavioral performances in the PD mice. Moreover, 16S RNA sequencing identified the increase of bacterial genera Akkermansia and Desulfovibrio in fecal samples of rotenone-induced mice. By contrast, FMT treatment remarkably restored the gut microbial community, thus ameliorating the gastrointestinal dysfunctions and the motor deficits of the PD mice. Further experiments revealed that FMT administration alleviated intestinal inflammation and barrier destruction, thus reducing the levels of systemic inflammation. Subsequently, FMT treatment attenuated blood-brain barrier (BBB) impairment and suppressed neuroinflammation in the substantia nigra (SN), which further decreased the damage of dopaminergic neurons. Additional mechanistic investigation discovered that FMT treatment reduced lipopolysaccharide (LPS) levels in the colon, the serum, and the SN, thereafter suppressing the TLR4/MyD88/NF-κB signaling pathway and its downstream pro-inflammatory products both in the SN and the colon.ConclusionsOur current study demonstrates that FMT treatment can correct the gut microbiota dysbiosis and ameliorate the rotenone-induced PD mouse model, in which suppression of the inflammation mediated by the LPS-TLR4 signaling pathway both in the gut and the brain possibly plays a significant role. Further, we prove that rotenone-induced microbiota dysbiosis is involved in the genesis of PD via the microbiota-gut-brain axis. Video abstract.

Dataset Information

P204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling in Mice.

Publications

p204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling in Mice.

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