Article
Immunology
Andrea N. Loes, Melissa N. Hinman, Dylan R. Farnsworth, Adam C. Miller, Karen Guillemin, Michael J. Harms
Summary: The zebrafish is a powerful model organism for studying the innate immune system. Recent findings suggest that zebrafish share an LPS-sensitive Tlr4/Md-2 complex with mammals, rather than a new invention in tetrapods. The discovery of the Ly96 gene in zebrafish and functional assays further support this hypothesis, indicating a low-sensitivity ancestral Tlr4/Md-2 complex retained by zebrafish.
JOURNAL OF IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Alessio Borio, Aurora Holgado, Christina Passegger, Herbert Strobl, Rudi Beyaert, Holger Heine, Alla Zamyatina
Summary: The TLR4/MD-2 complex is a crucial receptor in the innate immune system and plays a major role in inflammation, but dysregulation in its signaling can lead to uncontrolled inflammation and disease. Targeting this receptor complex with anti-inflammatory therapies is promising, but the complexity of ligand recognition and species-specificity presents challenges. Researchers have developed glycolipids that mimic lipid A and inhibit TLR4-mediated inflammation, and these glycolipids were evaluated for their activity in human and murine immune cells. A bis-phosphorylated glycolipid was found to have antagonist activity on human TLR4, but acted as a partial agonist on murine TLR4.
Article
Medicine, Research & Experimental
Wenxia Wang, Swarna Bale, Bharath Yalavarthi, Priyanka Verma, Pei-Suen Tsou, Ken M. Calderone, Dibyendu Bhattacharyya, Gary J. Fisher, John Varga, Swati Bhattacharyya
Summary: RP105 has been identified as a novel cell-intrinsic negative regulator of TLR4-MD2-driven sustained fibroblast activation, and its impaired function may contribute to the progression of systemic sclerosis.
Article
Multidisciplinary Sciences
Yang Bai, Rui Min, Pengcheng Chen, Shenglin Mei, Fan Deng, Zengzhang Zheng, Cong Jiang, Rui Miao, Zeyu Wu, Peng Zhang, Youdong Pan, Judy Lieberman, Xing Liu
Summary: We found that disulfiram (DSF) can inhibit TLR4-mediated inflammatory signaling and has significant anti-inflammatory effects and improves motor function in a Parkinson's disease model, suggesting the potential application of DSF in treating inflammation-related diseases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Lijing Su, Muhammad Athamna, Ying Wang, Junmei Wang, Marina Freudenberg, Tao Yue, Jianhui Wang, Eva Marie Y. Moresco, Haoming He, Tsaffrir Zor, Bruce Beutler
Summary: Sulfatides can activate mouse immune responses via the TLR4-MD-2 complex, but exhibit antagonistic effects in human cells. Their activity is related to the presence of the sulfate group and the length of the fatty acid chain, and their structure mimics the activation mechanism of molecules like LPS in receptors.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Mrityunjoy Biswas, Tatsuya Yamazaki, Susumu Tomono, Sivasundaram Karnan, Hidekazu Takagi, Isao Ichimonji, Masanori Inui, Fumiaki Nagaoka, Yoshitaka Hosokawa, Sachiko Akashi-Takamura
Summary: The cell surface expression of RP105, an orphan Toll-like receptor, depends on its complex formation with MD-1. N-glycosylation of MD-1 may serve as a potential target for SLE therapy.
Article
Immunology
Sachiko Watanabe, Kosuke Zenke, Masashi Muroi
Summary: In this study, a novel function of lipoteichoic acid (LTA) was discovered, which involves suppression of TLR4-mediated signaling independently of TLR2 under serum-free conditions. LTA promotes the association of MD-2 molecules to form an inactive TLR4/MD-2 complex dimer, thereby preventing TLR4-mediated signaling.
JOURNAL OF IMMUNOLOGY
(2023)
Article
Immunology
Yaxing Zhao, Peng Liu, Haofan Luan, Hua Jiang, Yingmei Xu, Yuanqiang Zhang, Yubin Zhang, Ruiyan Li
Summary: A study has found that demethyleneberberine (DMB) has potential anti-inflammatory effects and could be used to treat conditions such as colitis induced by TNBS. It was shown that DMB can inhibit the activation of the TLR4 signaling pathway by non-covalently binding to the MD-2 protein. Therefore, DMB may be a promising drug to suppress inflammatory response.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Cell Biology
Ting-Yu Cheng, Yen-Ju Lin, Wataru Saburi, Stefan Vieths, Stephan Scheurer, Stefan Schulke, Masako Toda
Summary: The study evaluated the immunological function of mannooligosaccharides with beta-(1 -> 4) bonds, finding that they can stimulate immune cells to produce various cytokines, enhance CD4(+) T cell stimulatory capacity, and promote pro-inflammatory cytokine production through glycolysis.
Article
Immunology
Jiefu Zhu, Yafei Zhang, Lang Shi, Yao Xia, Hongchu Zha, Huimin Li, Zhixia Song
Summary: This study reveals the protective role of RP105 in ischemic and septic acute kidney injury (AKI). Overexpression of RP105 alleviated renal structural injuries and dysfunction caused by ischemic and septic AKI. RP105 suppressed inflammatory responses mediated by the TLR4 signaling pathway. These findings suggest that RP105 could be a potential target for preventing and treating ischemic and septic AKI.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2022)
Article
Medicine, Research & Experimental
Kota Nakatomi, Hikari Ueno, Yuto Ishikawa, Ronny Christiadi Salim, Yuki Mori, Issey Kanemoto, Salunya Tancharoen, Kiyoshi Kikuchi, Naoki Miura, Taketo Omori, Emiko Okuda-Ashitaka, Kiyoshi Matsumura, Hitoshi Imaizumi, Yoshihiro Motomiya, Ikuro Maruyama, Ko-ichi Kawahara
Summary: NPM1 released from damaged cells or secreted by immune cells can stimulate inflammation by promoting cytokine production, possibly through TLR4 pathway. Inhibiting NPM1 activity may be a novel strategy for treating TLR4-related diseases, as suggested by the study findings on NPM1 signaling and its potential receptor TLR4.
BIOMEDICAL REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Tengyue Zhang, Siqi Xing, Jiyu Du, Jucheng Xia, Shuanghong Dong, Zeng Li, Zhicheng Liu, Yang Song
Summary: In this study, a receptor structure-based virtual screening strategy was developed to identify potential TLR/MD2 inhibitors for inflammatory diseases. Hit compound 94 exhibited promising anti-inflammatory activity and low toxicity, inhibiting the activation of TLR4/MD2-associated signaling pathways.
BIOORGANIC CHEMISTRY
(2023)
Review
Oncology
Mai Mahmoud Gabr, Iqira Saeed, Jared A. Miles, Benjamin P. Ross, Paul Nicholas Shaw, Markus W. Hollmann, Marie-Odile Parat
Summary: Recent evidence suggests that opioids can interact with the Toll-like receptor 4 (TLR4) on innate immune and cancer cells, potentially influencing tumor growth and metastasis. Opioids have been shown to weakly activate TLR4 and can inhibit its activation by lipopolysaccharide (LPS). The interaction of opioids with TLR4 is complex, involving non-competitive mechanisms and downstream effects on NF-kappa B activation.
Article
Chemistry, Medicinal
Dong Ding, Yu Wen, Chun-Miao Liao, Xu-Guang Yin, Ru-Yan Zhang, Jian Wang, Shi-Hao Zhou, Zhi-Ming Zhang, Yong-Ke Zou, Xiao-Fei Gao, Hua-Wei Wei, Guang-Fu Yang, Jun Guo
Summary: In this work, a new TLR4 agonist, GAP112, was synthesized as a potent adjuvant to enhance the immunogenicity of the SARS-CoV-2 spike RBD protein. The TLR4 agonist was conjugated to the protein antigen to create a liposomal formulation for vaccination. The conjugate vaccine significantly activated innate immune cells, induced a substantial increase in RBD-specific antibodies, and enhanced T-cell responses. Furthermore, the antibodies produced by the vaccine effectively neutralized SARS-CoV-2 variants.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Applied
Ian D. Young, Sergey A. Nepogodiev, Ian M. Black, Gwenaelle Le Gall, Alexandra Wittmann, Dimitrios Latousakis, Triinu Visnapuu, Parastoo Azadi, Robert A. Field, Nathalie Juge, Norihito Kawasaki
Summary: This study investigates the immunomodulatory properties of Levan and finds that its interaction with TLR4 through LPS mediates the immune response in immune cells.
CARBOHYDRATE POLYMERS
(2022)
Article
Biochemistry & Molecular Biology
Ankita Chadda, Alexander G. Kozlov, Binh Nguyen, Timothy M. Lohman, Eric A. Galburt
Summary: In this study, it was found that the DNA damage response in Mycobacterium tuberculosis differs from well-studied model bacteria. The DNA repair helicase UvrD1 in Mtb is activated through a redox-dependent process and is closely associated with the homo-dimeric Ku protein. Additionally, Ku protein is shown to stimulate the helicase activity of UvrD1.
JOURNAL OF MOLECULAR BIOLOGY
(2024)