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MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands.

ABSTRACT: Toll-like receptors (TLRs) trigger intestinal inflammation when the epithelial barrier is breached by physical trauma or pathogenic microbes. Although it has been shown that TLR-mediated signals are ultimately protective in models of acute intestinal inflammation [such as dextran sulfate sodium (DSS)-induced colitis], it is less clear which cells mediate protection. Here we demonstrate that TLR signaling in the nonhematopoietic compartment confers protection in acute DSS-induced colitis. Epithelial cells of MyD88/Trif-deficient mice express diminished levels of the epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG), and systemic lipopolysaccharide administration induces their expression in the colon. N-ethyl-N-nitrosourea (ENU)-induced mutations in Adam17 (which is required for AREG and EREG processing) and in Egfr both produce a strong DSS colitis phenotype, and the Adam17 mutation exerts its deleterious effect in the nonhematopoietic compartment. The effect of abrogation of TLR signaling is mitigated by systemic administration of AREG. A TLR?MyD88?AREG/EREG?EGFR signaling pathway is represented in nonhematopoietic cells of the intestinal tract, responds to microbial stimuli once barriers are breached, and mediates protection against DSS-induced colitis.

SUBMITTER: Brandl K

PROVIDER: S-EPMC2993336 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands.

Brandl Katharina K Sun Lei L Neppl Christina C Siggs Owen M OM Le Gall Sylvain M SM Tomisato Wataru W Li Xiaohong X Du Xin X Maennel Daniela N DN Blobel Carl P CP Beutler Bruce B

Proceedings of the National Academy of Sciences of the United States of America 20101101 46

Toll-like receptors (TLRs) trigger intestinal inflammation when the epithelial barrier is breached by physical trauma or pathogenic microbes. Although it has been shown that TLR-mediated signals are ultimately protective in models of acute intestinal inflammation [such as dextran sulfate sodium (DSS)-induced colitis], it is less clear which cells mediate protection. Here we demonstrate that TLR signaling in the nonhematopoietic compartment confers protection in acute DSS-induced colitis. Epithel ...[more]

PMID: 21041656

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Project description:BackgroundAccording to the Chinese Pharmacopoeia, the fruit of Schisandra chinensis (Turcz.) Baill. (SC) is an important traditional Chinese medicine that can be used to treat diarrhea. Despite the increasing research on the anti-inflammatory and anti-oxidant aspects of SC, the studies on the anti-ulcerative colitis of Schisandrin (SCH), the main constituent of SC, are relatively few.MethodsThe mice used in the study were randomly distributed into 6 groups: control, model, 5-ASA, and SCH (20, 40, 80 mg/kg/d). The mice in the model group were administered 3% (w/v) dextran sulfate sodium (DSS) through drinking water for 7 days, and the various parameters of disease activity index (DAI) such as body weight loss, stool consistency, and gross blood were measured. ELISA was used to detect inflammatory factors, and bioinformatics combined with transcriptome analysis was done to screen and verify relevant targets. 16S rDNA high-throughput sequencing was used to analyze the composition of the gut microbiota(GM), while mass spectrometry was done to analyze the changes in the content of bile acids (BAs) in the intestine.ResultsMice treated with SCH experienced significant weight gain, effectively alleviating the severity of colitis, and decreasing the levels of inflammatory factors such as TNF-α, IL-1β, IL-18, IL-6, and other related proteins (NLRP3, Caspase-1, SGK1) in UC mice. Furthermore, the analysis of GM and BAs in mice revealed that SCH increased the relative abundance of Lactobacilli spp, reduced the relative abundance of Bacteroides, and promoted the conversion of primary BAs to secondary BAs. These effects contributed to a significant improvement in the DSS-induced GM imbalance and the maintenance of intestinal homeostasis.ConclusionIt seems that there is a close relationship between the SCH mechanism and the regulation of SGK1/NLRP3 pathway and the restoration of GM balance. Therefore, it can be concluded that SCH could be a potential drug for the treatment of UC.

Project description:BackgroundPneumonia refers to the inflammation of the terminal airway, alveoli and pulmonary interstitium, which can be caused by pathogenic microorganisms, physical and chemical factors, immune damage, and drugs. Anemoside B4, the major ingredient of Pulsatilla chinensis (Bunge) Regel, exhibited anti-inflammatory activity. However, the therapeutic effect of anemoside B4 on pneumonia has not been unraveled. This study aims to investigate that anemoside B4 attenuates the inflammatory responses in Klebsiella pneumonia (KP)- and influenza virus FM1 (FM1)-induced pneumonia mice model.MethodsThe network pharmacology and molecular docking assays were employed to predict the targets of anemoside B4's treatment of pneumonia. Two models (bacterial KP-infected mice and virus FM1-infected mice) were employed in our study. BALB/c mice were divided into six groups: control, model group (KP-induced pneumonia or FM1-induced pneumonia), anemoside B4 (B4)-treated group (2.5, 5, 10 mg/kg), and positive drug group (ribavirin or ceftriaxone sodium injection). Blood samples were collected for hematology analysis. The effects of B4 on inflammation-associated mediators were investigated by Enzyme-linked immunosorbent assay (ELISA) and hematoxylin and eosin staining (HE) staining. Proteins expression was quantified by western blotting.ResultsThe network results indicated that many pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) participated in anemoside B4's anti-inflammatory activity. The counts of neutrophil (NEU) and white blood cell (WBC), the level of myeloperoxidase (MPO), and the release of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 increased by KP or FM1 infection, which were reversed by anemoside B4. In addition, anemoside B4 significantly suppressed the FM1-induced expression of toll-like receptor 4 (TLR4), myeloid differential protein-88 (MyD88), and myeloid differentiation protein-2 (MD-2), which were further validated by molecular docking data that anemoside B4 bound to bioactive sites of TLR4. Therefore, anemoside B4 exhibited a significant therapeutic effect on pneumonia via the TLR4/MyD88 pathway.ConclusionOur findings demonstrated that anemoside B4 attenuates pneumonia via the TLR4/Myd88 signaling pathway, suggesting that anemoside B4 is a promising therapeutic candidate for bacterial-infected or viral-infected pneumonia.

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MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands.

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MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands.

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