Function of TREM1 and TREM2 in Liver-Related Diseases

TREM1 and TREM2 are members of the triggering receptors expressed on myeloid cells (TREM) family. Both TREM1 and TREM2 are immunoglobulin superfamily receptors. Their main function is to identify foreign antigens and toxic substances, thereby adjusting the inflammatory response. In the liver, TREM1 and TREM2 are expressed on non-parenchymal cells, such as liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, and cells which infiltrate the liver in response to injury including monocyte-derived macrophages and neutrophils. The function of TREM1 and TREM2 in inflammatory response depends on Toll-like receptor 4. TREM1 mainly augments inflammation during acute inflammation, while TREM2 mainly inhibits chronic inflammation to protect the liver from pathological changes. Chronic inflammation often induces metabolic abnormalities, fibrosis, and tumorigenesis. The above physiological changes lead to liver-related diseases, such as liver injury, nonalcoholic steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma. Here, we review the function of TREM1 and TREM2 in different liver diseases based on inflammation, providing a more comprehensive perspective for the treatment of liver-related diseases.

Download Full-text

CD4+CD25+Foxp3+ regulatory T cells regulate immune balance in unexplained recurrent spontaneous abortion via the Toll-like receptor 4/nuclear factor-κB pathway

Journal of International Medical Research ◽

10.1177/0300060520980940 ◽

2020 ◽

Vol 48 (12) ◽

pp. 030006052098094

Author(s):

Shuang Qin ◽

Li Li ◽

Jia Liu ◽

Jinrui Zhang ◽

Qing Xiao ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Inflammatory Response ◽

Mouse Model ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Unexplained Recurrent Spontaneous Abortion ◽

Tlr4 Antagonist

Objective The present study aimed to evaluate the effects of cluster of differentiation (CD)4+CD25+ forkhead box p3 (Foxp3)+ regulatory T cells (Tregs) on unexplained recurrent spontaneous abortion (URSA) and the associated mechanisms. Methods The proportion of CD4+CD25+Foxp3+ Tregs and inflammatory cytokine concentrations in the peripheral blood of women with URSA were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. CBA/JxDBA/2J mating was used to establish an abortion-prone mouse model and the model mice were treated with the Toll-like receptor 4 (TLR4) antagonist E5564 and the TLR4 agonist lipopolysaccharide. Results The proportion of CD4+CD25+Foxp3+ Tregs was decreased and the inflammatory response was increased in women with URSA. In the abortion-prone mouse model, E5564 significantly increased the proportion of CD4+CD25+Foxp3+ Tregs, decreased the inflammatory response, and increased Foxp3 mRNA and protein expression. Lipopolysaccharide had adverse effects on the abortion-prone model. Conclusions These data suggest that CD4+CD25+Foxp3+ Tregs regulate immune homeostasis in URSA via the TLR4/nuclear factor-κB pathway, and that the TLR4 antagonist E5564 may be a novel and potential drug for treating URSA.

Download Full-text

Paralemmin-3 contributes to lipopolysaccharide-induced inflammatory response and is involved in lipopolysaccharide-Toll-like receptor-4 signaling in alveolar macrophages

International Journal of Molecular Medicine ◽

10.3892/ijmm.2017.3161 ◽

2017 ◽

Author(s):

Xu-Xin Chen ◽

Lu Tang ◽

Yu-Mei Fu ◽

Yi Wang ◽

Zhi-Hai Han ◽

...

Keyword(s):

Inflammatory Response ◽

Alveolar Macrophages ◽

Toll Like Receptor ◽

Toll Like Receptor 4

Download Full-text

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.

Download Full-text

Immunomodulatory Effects of Yersinia pestis Lipopolysaccharides on Human Macrophages

Clinical and Vaccine Immunology ◽

10.1128/cvi.00336-09 ◽

2009 ◽

Vol 17 (1) ◽

pp. 49-55 ◽

Cited By ~ 20

Author(s):

Motohiro Matsuura ◽

Hideyuki Takahashi ◽

Haruo Watanabe ◽

Shinji Saito ◽

Kazuyoshi Kawahara

Keyword(s):

Inflammatory Response ◽

Yersinia Pestis ◽

Lipid A ◽

Antagonistic Activity ◽

Gram Negative Bacteria ◽

Toll Like Receptor ◽

Defense System ◽

Toll Like Receptor 4 ◽

Bacterial Binding ◽

Binding Forms

ABSTRACTIn the current study, we investigated the activity of lipopolysaccharide (LPS) purified fromYersinia pestisgrown at either 27°C or 37°C (termed LPS-27 and LPS-37, respectively). LPS-27 containing hexa-acylated lipid A, similar to the LPS present in usual gram-negative bacteria, stimulated an inflammatory response in human U937 cells through Toll-like receptor 4 (TLR4). LPS-37, which did not contain hexa-acylated lipid A, exhibited strong antagonistic activity to the TLR4-mediated inflammatory response. The phagocytic activity in the cells was not affected by LPS-37. To estimate the activity of LPS in its bacterial binding form, formalin-killed bacteria (FKB) were prepared fromY. pestiscells grown at 27°C or 37°C (termed FKB-27 and FKB-37, respectively). FKB-27 strongly stimulated the inflammatory response. This activity was suppressed in the presence of an anti-TLR4 antibody but not an anti-TLR2 antibody. In addition, this activity was almost completely suppressed by LPS-37, indicating that the activity of FKB-27 is predominantly derived from the LPS-27 bacterial binding form. In contrast, FKB-37 showed no antagonistic activity. The results arising from the current study indicate thatY. pestiscauses infection in humans without stimulating the TLR4-based defense systemviabacterial binding of LPS-37, even when bacterial free LPS-37 is not released to suppress the defense system. This is in contrast to the findings for bacteria that possess agonistic LPS types, which are easily recognized by the defense systemviathe bacterial binding forms.

Download Full-text

Fas ligation on macrophages enhances IL-1R1–Toll-like receptor 4 signaling and promotes chronic inflammation

Nature Immunology ◽

10.1038/ni1054 ◽

2004 ◽

Vol 5 (4) ◽

pp. 380-387 ◽

Cited By ~ 98

Author(s):

Yingyu Ma ◽

Hongtao Liu ◽

Hoang Tu-Rapp ◽

Hans-Juergen Thiesen ◽

Saleh M Ibrahim ◽

...

Keyword(s):

Chronic Inflammation ◽

Toll Like Receptor ◽

Toll Like Receptor 4

Download Full-text

Toll-like receptor 4 plays a crucial role in the immune-adrenal response to systemic inflammatory response syndrome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0601527103 ◽

2006 ◽

Vol 103 (16) ◽

pp. 6392-6397 ◽

Cited By ~ 95

Author(s):

K. Zacharowski ◽

P. A. Zacharowski ◽

A. Koch ◽

A. Baban ◽

N. Tran ◽

...

Keyword(s):

Systemic Inflammatory Response Syndrome ◽

Inflammatory Response ◽

Crucial Role ◽

Systemic Inflammatory Response ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Adrenal Response

Download Full-text

Inflammation, innate immunity and blood coagulation

Hämostaseologie ◽

10.1055/s-0037-1617146 ◽

2010 ◽

Vol 30 (01) ◽

pp. 5-9 ◽

Cited By ~ 113

Author(s):

J. Xu ◽

F. Lupu ◽

C. T. Esmon

Keyword(s):

Innate Immunity ◽

Inflammatory Response ◽

Venous Thrombosis ◽

Organ Failure ◽

Blood Coagulation ◽

Chronic Inflammation ◽

Cell Apoptosis ◽

Acute Inflammation ◽

Microvascular Thrombosis ◽

Thrombotic Complications

SummaryInflammation drives arterial, venous and microvascular thrombosis. Chronic inflammation contributes to arterial thrombotic complications, whereas acute inflammation drives venous thrombosis and microvascular thrombosis. Mechanistically, inflammation modulates thrombotic responses by upregulating procoagulants, downregulating anticoagulants and suppressing fibrinolysis. The inflammatory response can also result in cell apoptosis or necrosis. Products released from the dead cells, particularly histones, propagate further inflammation, tissue death and organ failure.Inhibition of histone mediated cytotoxicity appears to be a new mechanism for protecting against this deadly cascade.

Download Full-text

Antiaging Factor Klotho Retards the Progress of Intervertebral Disc Degeneration through the Toll-Like Receptor 4-NF-κB Pathway

International Journal of Cell Biology ◽

10.1155/2020/8319516 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Fangfang Bi ◽

Wenbo Liu ◽

Zongtao Wu ◽

Chen Ji ◽

Cuicui Chang

Keyword(s):

Intervertebral Disc ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Acute Inflammation ◽

Protective Effects ◽

Toll Like Receptor ◽

Inhibitory Effects ◽

Toll Like Receptor 4 ◽

Disc Injury ◽

Anti Inflammation

Antiaging protein Klotho exhibits impressive properties of anti-inflammation, however is declined early after intervertebral disc injury, making Klotho restoration an attractive strategy of treating intervertebral disc inflammatory disorders. Here, we have found that Klotho is enriched in nucleus pulposus (NP) cells and Klotho overexpression attenuates H2O2-induced acute inflammation essentially via suppressing Toll-like receptor 4 (TLR4). The proinflammatory NF-κB signaling and cytokine expressions paralleled with Klotho repression and TLR4 elevation in both NP cells (H2O2 treatment) and rat intervertebral disc (needle puncture treatment). Overexpression of TLR4 downregulated expression of Klotho, whereas interfering TLR4 expression diminished the inhibitory effects of H2O2 on Klotho in NP cells. Consistently, Klotho knockdown by RNA interferences largely diminished the anti-inflammatory and intervertebral disc protective effects in an Intervertebral Disc Degeneration (IDD) model. Thus, our study indicates that TLR4-NF-κB signaling and Klotho form a negative-feedback loop in NP cells. Also, we demonstrate that the expression of Klotho is regulated by the balance between upregulation and downregulation of TLR4-NF-κB signaling.

Download Full-text