Lysozyme elicits pain during nerve injury by neuronal Toll-like receptor 4 activation and has therapeutic potential in neuropathic pain

2019 ◽  
Vol 11 (504) ◽  
pp. eaav4176 ◽  
Author(s):  
Saurabh Yadav ◽  
Avadhesha Surolia
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Neuronal Excitability ◽  
Therapeutic Potential ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
C Fibers ◽  
Enhanced Expression ◽  
Thermal Pain Sensitivity

The role of neuronal Toll-like receptor 4 (TLR4) in nerve injury is being pursued actively. However, the endogenous activation of neuronal TLR4 during neuroinflammation, in absence of the participation of glial TLR4, remains elusive. Here, we identified lysozyme as an endogenous activator of neuronal TLR4 signaling during nerve injury. Upon nerve injury, enhanced expression of lysozyme promoted neuronal hyperexcitability and neuropathic pain. Injections of lysozyme in healthy rats increased their mechanical and thermal pain sensitivity. Likewise, infusion of spinal cord slices with lysozyme increased neuronal excitability typical of neuropathic pain. Our results also showed that lysozyme activated excitability of both Aδ- and C-fibers. Thus, in addition to the discovery of lysozyme as an endogenous ligand for regulating neuronal TLR4 signaling, this study also lays the foundation of our understanding of its role in nervous system pathologies, providing multiple avenues for treating neuroinflammation.

scholarly journals (+)-Naloxone, an Opioid-Inactive Toll-Like Receptor 4 Signaling Inhibitor, Reverses Multiple Models of Chronic Neuropathic Pain in Rats

2012 ◽  
Vol 13 (5) ◽  
pp. 498-506 ◽  
Author(s):  
Susannah S. Lewis ◽  
Lisa C. Loram ◽  
Mark R. Hutchinson ◽  
Chien-Ming Li ◽  
Yingning Zhang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Multiple Models ◽  
Toll Like Receptor ◽  
Chronic Neuropathic Pain ◽  
Toll Like Receptor 4

scholarly journals Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis

2021 ◽  
Vol 13 (599) ◽  
pp. eabe1692
Author(s):  
Junjie Yu ◽  
Changyu Zhu ◽  
Xiaobo Wang ◽  
KyeongJin Kim ◽  
Alberto Bartolome ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
High Fat Diet ◽  
Therapeutic Potential ◽  
Nuclear Factor Κb ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Nonalcoholic Fatty Liver ◽  
Biopsy Specimens ◽  
Nafld Activity Score ◽  
Notch Activation

Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)–induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 (JAG1) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)–nuclear factor κB (NF-κB) signaling in pericentral hepatocytes. Hepatocyte-specific Jag1 overexpression exacerbated fibrosis in mice fed a high-fat diet or a NASH-provoking diet rich in palmitate, cholesterol, and sucrose and reversed the protection afforded by hepatocyte-specific TLR4 deletion, whereas hepatocyte-specific Jag1 knockout mice were protected from NASH-induced liver fibrosis. To test therapeutic potential of this biology, we designed a Jag1-directed antisense oligonucleotide (ASO) and a hepatocyte-specific N-acetylgalactosamine (GalNAc)–modified siRNA, both of which reduced NASH diet–induced liver fibrosis in mice. Overall, these data demonstrate that increased hepatocyte Jagged1 is the proximal hit for Notch-induced liver fibrosis in mice and suggest translational potential of Jagged1 inhibitors in patients with NASH.

Monitoring of macrophage recruitment enhanced by Toll-like receptor 4 activation with MR imaging in nerve injury

2018 ◽  
Vol 58 (1) ◽  
pp. 123-132 ◽  
Author(s):  
Mei-Wei Chen ◽  
Xiang Zhang ◽  
Lie-Jing Lu ◽  
Fang Zhang ◽  
Xiao-Hui Duan ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Nerve Injury ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Macrophage Recruitment

scholarly journals Toll-Like Receptor 4 Signaling and Drug Addiction

2020 ◽  
Vol 11 ◽  
Author(s):  
Ruyan Wu ◽  
Jun-Xu Li
Keyword(s):  
Drug Addiction ◽  
Multiple Drug ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Drug Classes ◽  
Downstream Effectors ◽  
Potential Efficacy ◽  
Proinflammatory Responses

The emphasis of neuronal alterations and adaptations have long been the main focus of the studies of the mechanistic underpinnings of drug addiction. Recent studies have begun to appreciate the role of innate immune system, especially toll-like receptor 4 (TLR4) signaling in drug reward-associated behaviors and physiology. Drugs like opioids, alcohol and psychostimulants activate TLR4 signaling and subsequently induce proinflammatory responses, which in turn contributes to the development of drug addiction. Inhibition of TLR4 or its downstream effectors attenuated the reinforcing effects of opioids, alcohol and psychostimulants, and this effect is also involved in the withdrawal and relapse-like behaviors of different drug classes. However, conflicting results also argue that TLR4-related immune response may play a minimal part in drug addiction. This review discussed the preclinical evidence that whether TLR4 signaling is involved in multiple drug classes action and the possible mechanisms underlying this effect. Moreover, clinical studies which examined the potential efficacy of immune-base pharmacotherapies in treating drug addiction are also discussed.

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

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.

scholarly journals Amphiphilic Guanidinocalixarenes Inhibit Lipopolysaccharide (LPS)- and Lectin-Stimulated Toll-like Receptor 4 (TLR4) Signaling

2017 ◽  
Vol 60 (12) ◽  
pp. 4882-4892 ◽  
Author(s):  
Stefania E. Sestito ◽  
Fabio A. Facchini ◽  
Ilaria Morbioli ◽  
Jean-Marc Billod ◽  
Sonsoles Martin-Santamaria ◽  
...  
Keyword(s):  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling

scholarly journals Endotoxin Tolerance Inhibits Lyn and c-Src Phosphorylation and Association with Toll-Like Receptor 4 but Increases Expression and Activity of Protein Phosphatases

2015 ◽  
Vol 8 (2) ◽  
pp. 171-184 ◽  
Author(s):  
Yanbao Xiong ◽  
Michael Murphy ◽  
Tissa T. Manavalan ◽  
Goutham Pattabiraman ◽  
Fu Qiu ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Protein Phosphatase ◽  
Tyrosine Phosphatase ◽  
Endotoxin Tolerance ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Mitogen Activated Protein ◽  
Ptp 1B

Endotoxin tolerance protects the host by limiting excessive 'cytokine storm' during sepsis, but compromises the ability to counteract infections in septic shock survivors. It reprograms Toll-like receptor (TLR) 4 responses by attenuating the expression of proinflammatory cytokines without suppressing anti-inflammatory and antimicrobial mediators, but the mechanisms of reprogramming remain unclear. In this study, we demonstrate that the induction of endotoxin tolerance in human monocytes, THP-1 and MonoMac-6 cells inhibited lipopolysaccharide (LPS)-mediated phosphorylation of Lyn, c-Src and their recruitment to TLR4, but increased total protein phosphatase (PP) activity and the expression of protein tyrosine phosphatase (PTP) 1B, PP2A, PTP nonreceptor type (PTPN) 22 and mitogen-activated protein kinase phosphatase (MKP)-1. Chemical PP inhibitors, okadaic acid, dephostatin and cantharidic acid markedly decreased or completely abolished LPS tolerance, indicating the importance of phosphatases in endotoxin tolerization. Overexpression of PTPN22 decreased LPS-mediated nuclear factor (NF)-κB activation, p38 phosphorylation and CXCL8 gene expression, while PTPN22 ablation upregulated LPS-induced p65 NF-κB and p38 phosphorylation and the expression of TNF-a and pro-IL-1ß mRNA, indicating PTPN22 as an inhibitor of TLR4 signaling. Thus, LPS tolerance interferes with TLR4 signaling by inhibiting Lyn and c-Src phosphorylation and their recruitment to TLR4, while increasing the phosphatase activity and expression of PP2A, PTPN22, PTP1B and MKP1.

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