Human resistin protects against endotoxic shock by blocking LPS–TLR4 interaction

Helminths trigger multiple immunomodulatory pathways that can protect from sepsis. Human resistin (hRetn) is an immune cell-derived protein that is highly elevated in helminth infection and sepsis. However, the function of hRetn in sepsis, or whether hRetn influences helminth protection against sepsis, is unknown. Employing hRetn-expressing transgenic mice (hRETNTg+) and recombinant hRetn, we identify a therapeutic function for hRetn in lipopolysaccharide (LPS)-induced septic shock. hRetn promoted helminth-induced immunomodulation, with increased survival of Nippostrongylus brasiliensis (Nb)-infected hRETNTg+ mice after a fatal LPS dose compared with naive mice or Nb-infected hRETNTg− mice. Employing immunoprecipitation assays, hRETNTg+Tlr4−/− mice, and human immune cell culture, we demonstrate that hRetn binds the LPS receptor Toll-like receptor 4 (TLR4) through its N terminal and modulates STAT3 and TBK1 signaling, triggering a switch from proinflammatory to anti-inflammatory responses. Further, we generate hRetn N-terminal peptides that are able to block LPS proinflammatory function. Together, our studies identify a critical role for hRetn in blocking LPS function with important clinical significance in helminth-induced immunomodulation and sepsis.

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Critical role of toll-like receptor 4 (TLR4) in ricin toxin-induced inflammatory responses in macrophages

Toxicology Letters ◽

10.1016/j.toxlet.2019.12.021 ◽

2020 ◽

Vol 321 ◽

pp. 54-60 ◽

Cited By ~ 2

Author(s):

Mingxin Dong ◽

Haotian Yu ◽

Yan Wang ◽

Chengbiao Sun ◽

Ying Chang ◽

...

Keyword(s):

Inflammatory Responses ◽

Critical Role ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Ricin Toxin

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Faculty Opinions recommendation of Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1283990.751098 ◽

2009 ◽

Author(s):

Matthias Ochs ◽

Christian Mühlfeld

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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SARS-CoV-2 spike protein S1 subunit induces pro-inflammatory responses via toll-like receptor 4 signaling in murine and human macrophages

Heliyon ◽

10.1016/j.heliyon.2021.e06187 ◽

2021 ◽

Vol 7 (2) ◽

pp. e06187 ◽

Cited By ~ 2

Author(s):

Ken Shirato ◽

Takako Kizaki

Keyword(s):

Inflammatory Responses ◽

Spike Protein ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Human Macrophages

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Biofilm Growth Increases Phosphorylcholine Content and Decreases Potency of Nontypeable Haemophilus influenzae Endotoxins

Infection and Immunity ◽

10.1128/iai.74.3.1828-1836.2006 ◽

2006 ◽

Vol 74 (3) ◽

pp. 1828-1836 ◽

Cited By ~ 42

Author(s):

Shayla West-Barnette ◽

Andrea Rockel ◽

W. Edward Swords

Keyword(s):

Haemophilus Influenzae ◽

Inflammatory Responses ◽

Opportunistic Pathogen ◽

Host Responses ◽

Toll Like Receptor ◽

Nontypeable Haemophilus Influenzae ◽

Toll Like Receptor 4 ◽

Biofilm Growth ◽

Bacterial Endotoxins ◽

Cell Layers

ABSTRACT Nontypeable Haemophilus influenzae (NTHI) is a common respiratory commensal and opportunistic pathogen. NTHI is normally contained within the airways by host innate defenses that include recognition of bacterial endotoxins by Toll-like receptor 4 (TLR4). NTHI produces lipooligosaccharide (LOS) endotoxins which lack polymeric O side chains and which may contain host glycolipids. We recently showed that NTHI biofilms contain variants with sialylated LOS glycoforms that are essential to biofilm formation. In this study, we show that NTHI forms biofilms on epithelial cell layers. Confocal analysis revealed that sialylated variants were distributed throughout the biofilm, while variants expressing phosphorylcholine (PCho) were found within the biofilm. Consistent with this observation, PCho content of LOS purified from NTHI biofilms was increased compared to LOS from planktonic cultures. Hypothesizing that the observed changes in endotoxin composition could affect bioactivity, we compared inflammatory responses to NTHI LOS purified from biofilm and planktonic cultures. Our results show that endotoxins from biofilms induced weaker host innate responses. While we observed a minimal effect of sialylation on LOS bioactivity, there was a significant decrease in bioactivity associated with PCho substitutions. We thus conclude that biofilm growth increases the proportion of PCho+ variants in an NTHI population, resulting in a net decrease in LOS bioactivity. Thus, in addition to their well-documented resistance phenotypes, our data show that biofilm communities of NTHI bacteria contain variants that evoke less potent host responses.

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Abstract 2874: Functional Polymorphisms in Toll-like Receptor 4 Predict Worse Outcome in Acute Ischemic Stroke Patients

Stroke ◽

10.1161/str.43.suppl_1.a2874 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Jonathan R Weinstein ◽

Juliane Schulze ◽

Richard V Lee ◽

Dannielle Zierath ◽

Patricia Tanzi ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Immune Cell ◽

Stroke Severity ◽

Multiple Time ◽

Toll Like Receptor ◽

C Reactive Protein ◽

Toll Like Receptor 4 ◽

Reactive Protein ◽

Functional Polymorphisms

Background: Toll-like receptor-4 (TLR4) plays a central role in the pathophysiology of acute ischemic stroke (AIS). Specific single nucleotide polymorphisms (SNPs) in TLR4 including 1063 A/G [Asp299Gly] and 1363 C/T [Thr399Ile] alter immune cell responsiveness to lipopolysaccharide (LPS) and are associated with increased rates of infection. The effect of these TLR4 SNPs on outcome following AIS is unknown. Methods: Patients were prospectively enrolled after onset of AIS. Clinical and demographic data were collected and neurological outcomes assessed at 3 months. Blood was drawn at multiple time points to quantify leukocyte subsets and assess plasma levels of C-reactive protein and a panel of cytokines. Genotyping for the TLR4 SNPs was also performed on blood samples. Uni- and multivariate analyses were performed to assess associations between TLR4 SNP haplotype and (i) each laboratory parameter noted above, (ii) infection risk and (iii) stroke outcome. Results: Of the 42 patients included; 6 (14%) were heterozygous for either one or both TLR4 SNPs. Baseline characteristics were similar in patients with or without a TLR4 SNP. In analyses adjusted for both initial stroke severity and age, the presence of a TLR4 SNP was associated with increases in blood leukocytes, plasma C-reactive protein and the cytokine interleukin-1 receptor antagonist (IL-1ra). The presence of either TLR4 SNP was also associated with a trend toward increased rates of infection (adjusted odds ratio and 95% confidence interval of 8.20 and 0.826-81.5, respectively) and a decreased likelihood of favorable outcome as defined by a modified Rankin Scale score of two or less at three months from stroke onset (0.014, 0.00-0.759). Conclusions: In AIS patients, functionally significant genetic variations in TLR4 influence both rates of stroke-associated infection and neurological outcome. These data suggest a direct connection between TLR4 function and stroke pathophysiology.

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Key Player in Cardiac Hypertrophy, Emphasizing the Role of Toll-Like Receptor 4

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2020.579036 ◽

2020 ◽

Vol 7 ◽

Author(s):

Zheng Xiao ◽

Bin Kong ◽

Hongjie Yang ◽

Chang Dai ◽

Jin Fang ◽

...

Keyword(s):

Inflammatory Response ◽

Cardiac Hypertrophy ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

New Technologies ◽

Immune Cell ◽

Current Knowledge ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Tlr4 Signaling

Toll-like receptor 4 (TLR4), a key pattern recognition receptor, initiates the innate immune response and leads to chronic and acute inflammation. In the past decades, accumulating evidence has implicated TLR4-mediated inflammatory response in regulation of myocardium hypertrophic remodeling, indicating that regulation of the TLR4 signaling pathway may be an effective strategy for managing cardiac hypertrophy's pathophysiology. Given TLR4's significance, it is imperative to review the molecular mechanisms and roles underlying TLR4 signaling in cardiac hypertrophy. Here, we comprehensively review the current knowledge of TLR4-mediated inflammatory response and its interaction ligands and co-receptors, as well as activation of various intracellular signaling. We also describe the associated roles in promoting immune cell infiltration and inflammatory mediator secretion, that ultimately cause cardiac hypertrophy. Finally, we provide examples of some of the most promising drugs and new technologies that have the potential to attenuate TLR4-mediated inflammatory response and prevent or reverse the ominous cardiac hypertrophy outcomes.

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Critical role of toll-like receptor 4 (TLR4) in dextran sulfate sodium (DSS)-Induced intestinal injury and repair

Toxicology Letters ◽

10.1016/j.toxlet.2019.08.012 ◽

2019 ◽

Vol 315 ◽

pp. 23-30 ◽

Cited By ~ 6

Author(s):

Yun-Jie Shi ◽

Hai-Feng Gong ◽

Quan-Quan Zhao ◽

Xiao-Shuang Liu ◽

Cong Liu ◽

...

Keyword(s):

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Critical Role ◽

Intestinal Injury ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Injury And Repair

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Bacteroides fragilis-Derived Lipopolysaccharide Produces Cell Activation and Lethal Toxicity via Toll-Like Receptor 4

Infection and Immunity ◽

10.1128/iai.73.9.5620-5627.2005 ◽

2005 ◽

Vol 73 (9) ◽

pp. 5620-5627 ◽

Cited By ~ 43

Author(s):

Giuseppe Mancuso ◽

Angelina Midiri ◽

Carmelo Biondo ◽

Concetta Beninati ◽

Maria Gambuzza ◽

...

Keyword(s):

Cell Activation ◽

Cytokine Production ◽

Biological Activities ◽

Endotoxic Shock ◽

Intestinal Flora ◽

Bacteroides Fragilis ◽

Peritoneal Macrophages ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

In Cells

ABSTRACT Bacteroides fragilis, which is part of the normal intestinal flora, is a frequent cause of serious disease, especially in diabetic and surgical patients. In these conditions, B. fragilis lipopolysaccharide (LPS) is likely to play a major pathophysiologic role. B. fragilis LPS is structurally different from classical enterobacterial LPS, whose biological activities are mediated by Toll-like receptor 4 (TLR4) activation. The ability of B. fragilis LPS to activate TLR4 and TLR2 was investigated here, since evidence on this issue is scarce and controversial. Each of four different protein-free B. fragilis LPS preparations could induce interleukin-8 responses in cells cotransfected with TLR4/CD14/MD2 but not TLR4/CD14 alone. Two of the preparations also induced cytokine production in cells cotransfected with TLR2/CD14 or in peritoneal macrophages from TLR4 mutant C3H/HeJ mice. Both of these activities, however, were lost after repurification with a modified phenol reextraction procedure. Importantly, all preparations could induce endotoxic shock in TLR2-deficient mice, but not in TLR4 mutant C3H/HeJ mice. Consistent with these findings, anti-TLR4 and anti-CD14, but not anti-TLR2, antibodies could inhibit B. fragilis LPS-induced cytokine production in human monocytes. Collectively, these results indicate that B. fragilis LPS signals via a TLR4/CD14/MD2-dependent pathway, and it is unable to activate TLR2. Moreover, our data document the occurrence of TLR2-activating contaminants even in highly purified B. fragilis LPS preparations. This may explain earlier contradictory findings on the ability of B. fragilis LPS to activate cells in the absence of functional TLR4. These data may be useful to devise strategies to prevent the pathophysiologic changes observed during B. fragilis sepsis and to better understand structure-activity relationships of LPS.

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