TLR4 monoclonal antibody blockade suppresses dextran‐sulfate‐sodium‐induced colitis in mice

Liu, Yi; Zhang, Zhijun; Wang, Lei; Li, Juan; Dong, Lijie; Yue, Wenjie; Chen, Jian; Sun, Xiaofen; Liu, Zhong; Sun, Dongmei

doi:10.1111/j.1440-1746.2009.06046.x

Cited by 37 publications

(27 citation statements)

References 22 publications

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“…Trauma-induced TLR4 signaling in enterocytes leads to intestinal inflammation. We (23,43) and others (11,18,22,30,46) have recently demonstrated that small intestinal epithelial cells express TLR4 and that TLR4 activation within enterocytes leads to epithelial barrier disruption. On the basis of this prior work and in view of the findings of Fig.…”

Section: Remote Trauma Leads To Tlr4 Activation In the Intestinal Mucmentioning

confidence: 98%

DNA attenuates enterocyte Toll-like receptor 4-mediated intestinal mucosal injury after remote trauma

Sodhi

Levy

Gill

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Intestinal mucosal injury occurs after remote trauma although the mechanisms that sense remote injury and lead to intestinal epithelial disruption remain incompletely understood. We now hypothesize that Toll-like receptor 4 (TLR4) signaling on enterocytes after remote injury, potentially through the endogenous TLR4 ligand high-mobility group box-1 (HMGB1), could lead to intestinal dysfunction and bacterial translocation and that activation of TLR9 with DNA could reverse these effects. In support of this hypothesis, exposure of TLR4-expressing mice to bilateral femur fracture and systemic hypotension resulted in increased TLR4 expression and signaling and disruption of the ileal mucosa, leading to bacterial translocation, which was not observed in TLR4-mutant mice. TLR4 signaling in enterocytes, not immune cells, was required for this effect, as adenoviral-mediated inhibition of TLR4 in enterocytes prevented these findings. In seeking to identify the endogenous TLR4 ligands involved, the expression of HMGB1 was increased in the intestinal mucosa after injury in wild-type, but not TLR4-mutant, mice, and administration of anti-HMGB1 antibodies reduced both intestinal mucosal TLR4 signaling and bacterial translocation after remote trauma. Strikingly, mucosal injury was significantly increased in TLR9-mutant mice, whereas administration of exogenous DNA reduced the extent of TLR4-mediated enterocyte apoptosis, restored mucosal healing, and maintained the histological integrity of the intestinal barrier after remote injury. Taken together, these findings identify a novel link between remote injury and enterocyte TLR4 signaling leading to barrier injury, potentially through HMGB1 as a ligand, and demonstrate the reversal of these adverse effects through activation of TLR9.

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Section: Remote Trauma Leads To Tlr4 Activation In the Intestinal Mucmentioning

confidence: 98%

DNA attenuates enterocyte Toll-like receptor 4-mediated intestinal mucosal injury after remote trauma

Sodhi

Levy

Gill

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Inflammatory bowel disease has been associated with an increase in TLR4 activation (11), and therefore, we determined if feces from an IBD mouse model were altered in their capacity to activate TLR4 (Fig. 6A).…”

Section: Figmentioning

confidence: 99%

“…However, the mechanisms by which the host protects intestinal tissues from LPS exposure are impaired in certain forms of inflammatory bowel disease (IBD). For example, anti-TLR4 antibodies have been shown to reduce intestinal damage in dextran sodium sulfate (DSS)-treated mice (11), consistent with a significant increase in water-soluble pattern recognition receptor ligands in the feces of DSS-treated mice, such as the LPS receptor TLR4 (12). Similarly, in humans, individuals with Crohn's disease have increased circulating levels of MD-2, a key LPS coreceptor for TLR4 which results in significantly increased TLR4-dependent intestinal epithelial cell responses in vitro (13).…”

mentioning

confidence: 99%

Cardiolipins Act as a Selective Barrier to Toll-Like Receptor 4 Activation in the Intestine

Coats

Hashim

Paramonov

et al. 2016

Appl Environ Microbiol

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Intestinal homeostasis mechanisms must protect the host intestinal tissue from endogenous lipopolysaccharides (LPSs) produced by the intestinal microbiota. In this report, we demonstrate that murine intestinal fecal lipids effectively block Toll-like receptor 4 (TLR4) responses to naturally occurring Bacteroidetes sp. LPS. Cardiolipin (CL) represents a significant proportion of the total intestinal and fecal lipids and, furthermore, potently antagonizes TLR4 activation by reducing LPS binding at the lipopolysaccharide binding protein (LBP), CD14, and MD-2 steps of the TLR4 signaling pathway. It is further demonstrated that intestinal lipids and CL are less effective at neutralizing more potent Enterobacteriaceae-type LPS, which is enriched in feces obtained from mice with dextran sodium sulfate (DSS)-treated inflammatory bowel disease. The selective inhibition of naturally occurring LPS structures by intestinal lipids may represent a novel homeostasis mechanism that blocks LPS activation in response to symbiotic but not dysbiotic microbial communities. IMPORTANCEThe guts of animals harbor a variety of Gram-negative bacteria associated with both states of intestinal health and states of disease. Environmental factors, such as dietary habits, can drive the microbial composition of the host animal's intestinal bacterial community toward a more pathogenic state. Both beneficial and harmful Gram-negative bacteria are capable of eliciting potentially damaging inflammatory responses from the host intestinal tissues via a lipopolysaccharide (LPS)-dependent pathway. Physical mucosal barriers and antibodies produced by the intestinal immune system protect against the undesired inflammatory effects of LPS, although it is unknown why some bacteria are more effective at overcoming the protective barriers than others. This report describes the discovery of a lipid-type protective barrier in the intestine that reduces the deleterious effects of LPSs from beneficial bacteria but is less effective in dampening the inflammatory effects of LPSs from harmful bacteria, providing a novel mechanistic insight into inflammatory intestinal disorders.T he intestinal tract is constantly exposed to the potentially harmful effects of lipopolysaccharide (LPS), commonly referred to as endotoxin. Both internal sources, such as the intestinal microbiome, and external sources, such as food, provide a constant potential for endotoxin-mediated local or systemic injury. Several different innate and adaptive protective mechanisms present in the intestine facilitate a homeostatic relationship with the resident commensal microbiota and buffer food intake such that LPS does not impair normal intestinal tissue functions (1-5).Studies have shown that a major mechanism by which the intestine limits exposure to the potentially harmful effects of LPS is by preventing intestinal LPS-epithelial cell interactions through a physiochemical barrier consisting of a family of glycoproteins referred to as mucins. Mucins provide an effective barricade restrict...

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“…In addition, TLR4 is indicated to be linked with MAPK pathway in IBD. TLR4 monoclonal antibody (TLR4mAb) ameliorates DSS-induced colitis via suppression of p38 MAPK pathway (21). TLR4 ligand LPS caused significant phosphorylation (activation) of MAPK in intestinal mucosal enterochromaffin cells isolated from Crohn's colitis patients (18).…”

mentioning

confidence: 99%

Paeoniflorin abrogates DSS-induced colitis via a TLR4-dependent pathway

Zhang

Dou

Zhang

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

111

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Paeonia lactiflora Pall is one of the most well-known herbs in China, Korea, and Japan for more than 1,200 years. Paeoniflorin, the major bioactive component of peony root, has recently been reported to have anticolitic activity. However, the underlying molecular mechanism is unclear. The present study was to explore the possible mechanism of paeoniflorin in attenuating dextran sulfate sodium (DSS)-induced colitis. Pre- and coadministration of paeoniflorin significantly reduced the severity of colitis and resulted in downregulation of several inflammatory parameters in the colon, including the activity of myeloperoxidase (MPO), the levels of TNF-α and IL-6, and the mRNA expression of proinflammatory mediators (MCP-1, Cox2, IFN-γ, TNF-α, IL-6, and IL-17). The decline in the activation of NF-κB p65, ERK, JNK, and p38 MAPK correlated with a decrease in mucosal Toll-like receptor 4 (TLR4) but not TLR2 or TLR5 expression. In accordance with the in vivo results, paeoniflorin downregulated TLR4 expression, blocked nuclear translocation of NF-κB p65, and reduced the production of IL-6 in LPS-stimulated mouse macrophage RAW264.7 cells. Transient transfection assay performed in LPS-stimulated human colon cancer HT-29 cells indicated that paeoniflorin inhibits NF-κB transcriptional activity in a dose-dependent manner. TLR4 knockdown and overexpression experiments demonstrated a requirement for TLR4 in paeoniflorin-mediated downregulation of inflammatory cytokines. Thus, for the first time, the present study indicates that paeoniflorin abrogates DSS-induced colitis via decreasing the expression of TLR4 and suppressing the activation of NF-κB and MAPK pathways.

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TLR4 monoclonal antibody blockade suppresses dextran‐sulfate‐sodium‐induced colitis in mice

Abstract: Blocking TLR4 by TLR4mAb can prevent the development of DSS-induced colitis through the TLR4-P38MAPK-c-jun pathway.

Cited by 37 publications

References 22 publications

DNA attenuates enterocyte Toll-like receptor 4-mediated intestinal mucosal injury after remote trauma

DNA attenuates enterocyte Toll-like receptor 4-mediated intestinal mucosal injury after remote trauma

Cardiolipins Act as a Selective Barrier to Toll-Like Receptor 4 Activation in the Intestine

Paeoniflorin abrogates DSS-induced colitis via a TLR4-dependent pathway

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