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TLR4 activation by lysozyme induces pain without inflammation

Mostly, pain has been studied in association with inflammation, until recent studies which indicate that during bacterial infections, pain mechanisms could be independent of the inflammation. Chronic pain can sustain long after the healing from the injury, even in the absence of any visible inflamma...

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Autores principales: Yadav, Saurabh, Singh, Amrita, Kant, Ravi, Surolia, Avadhesha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10183575/
https://www.ncbi.nlm.nih.gov/pubmed/37197666
http://dx.doi.org/10.3389/fimmu.2023.1065226
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author Yadav, Saurabh
Singh, Amrita
Kant, Ravi
Surolia, Avadhesha
author_facet Yadav, Saurabh
Singh, Amrita
Kant, Ravi
Surolia, Avadhesha
author_sort Yadav, Saurabh
collection PubMed
description Mostly, pain has been studied in association with inflammation, until recent studies which indicate that during bacterial infections, pain mechanisms could be independent of the inflammation. Chronic pain can sustain long after the healing from the injury, even in the absence of any visible inflammation. However, the mechanism behind this is not known. We tested inflammation in lysozyme-injected mice foot paw. Interestingly, we observed no inflammation in mice foot paw. Yet, lysozyme injections induced pain in these mice. Lysozyme induces pain in a TLR4-dependent manner and TLR4 activation by its ligands such as LPS leads to inflammatory response. We compared the intracellular signaling of MyD88 and TRIF pathways upon TLR4 activation by lysozyme and LPS to understand the underlying mechanism behind the absence of an inflammatory response upon lysozyme treatment. We observed a TLR4 induced selective TRIF and not MyD88 pathway activation upon lysozyme treatment. This is unlike any other previously known endogenous TLR4 activators. A selective activation of TRIF pathway by lysozyme induces weak inflammatory cytokine response devoid of inflammation. However, lysozyme activates glutamate oxaloacetate transaminase-2 (GOT2) in neurons in a TRIF-dependent manner, resulting in enhanced glutamate response. We propose that this enhanced glutaminergic response could lead to neuronal activation resulting in pain sensation upon lysozyme injections. Collectively we identify that TLR4 activation by lysozyme can induce pain in absence of a significant inflammation. Also, unlike other known TLR4 endogenous activators, lysozyme does not activate MyD88 signaling. These findings uncover a mechanism of selective activation of TRIF pathway by TLR4. This selective TRIF activation induces pain with negligible inflammation, constituting a chronic pain homeostatic mechanism.
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spelling pubmed-101835752023-05-16 TLR4 activation by lysozyme induces pain without inflammation Yadav, Saurabh Singh, Amrita Kant, Ravi Surolia, Avadhesha Front Immunol Immunology Mostly, pain has been studied in association with inflammation, until recent studies which indicate that during bacterial infections, pain mechanisms could be independent of the inflammation. Chronic pain can sustain long after the healing from the injury, even in the absence of any visible inflammation. However, the mechanism behind this is not known. We tested inflammation in lysozyme-injected mice foot paw. Interestingly, we observed no inflammation in mice foot paw. Yet, lysozyme injections induced pain in these mice. Lysozyme induces pain in a TLR4-dependent manner and TLR4 activation by its ligands such as LPS leads to inflammatory response. We compared the intracellular signaling of MyD88 and TRIF pathways upon TLR4 activation by lysozyme and LPS to understand the underlying mechanism behind the absence of an inflammatory response upon lysozyme treatment. We observed a TLR4 induced selective TRIF and not MyD88 pathway activation upon lysozyme treatment. This is unlike any other previously known endogenous TLR4 activators. A selective activation of TRIF pathway by lysozyme induces weak inflammatory cytokine response devoid of inflammation. However, lysozyme activates glutamate oxaloacetate transaminase-2 (GOT2) in neurons in a TRIF-dependent manner, resulting in enhanced glutamate response. We propose that this enhanced glutaminergic response could lead to neuronal activation resulting in pain sensation upon lysozyme injections. Collectively we identify that TLR4 activation by lysozyme can induce pain in absence of a significant inflammation. Also, unlike other known TLR4 endogenous activators, lysozyme does not activate MyD88 signaling. These findings uncover a mechanism of selective activation of TRIF pathway by TLR4. This selective TRIF activation induces pain with negligible inflammation, constituting a chronic pain homeostatic mechanism. Frontiers Media S.A. 2023-05-01 /pmc/articles/PMC10183575/ /pubmed/37197666 http://dx.doi.org/10.3389/fimmu.2023.1065226 Text en Copyright © 2023 Yadav, Singh, Kant and Surolia https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Yadav, Saurabh
Singh, Amrita
Kant, Ravi
Surolia, Avadhesha
TLR4 activation by lysozyme induces pain without inflammation
title TLR4 activation by lysozyme induces pain without inflammation
title_full TLR4 activation by lysozyme induces pain without inflammation
title_fullStr TLR4 activation by lysozyme induces pain without inflammation
title_full_unstemmed TLR4 activation by lysozyme induces pain without inflammation
title_short TLR4 activation by lysozyme induces pain without inflammation
title_sort tlr4 activation by lysozyme induces pain without inflammation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10183575/
https://www.ncbi.nlm.nih.gov/pubmed/37197666
http://dx.doi.org/10.3389/fimmu.2023.1065226
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