This preprint is under consideration at Journal of Neuroinflammation. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
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Inhibition of TLR4 Signaling Protects Mice From Sensory and Motor Dysfunction in an Animal Model of Autoimmune Peripheral Neuropathy
Ji Zhang
McGill University
Corresponding Author
ORCiD: https://orcid.org/0000-0001-8816-9721
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
While the etiology remains elusive, macrophages and T cells in peripheral nerves are considered as effector cells mediating autoimmune peripheral neuropathy (APN), such as Guillain Barre Syndrome. By recognizing both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) signals, TLRs play a central role in the initiation of both innate and adaptive immune responses. In this study, we aimed to understand the involvement of TLR4 in the pathogenesis of APN and explore the potential of TLR4 as a drug target for therapeutic use.
Methods
APN was induced by a partial ligation on one of the sciatic nerves in B7.2 (L31) transgenic mice which possess a predisposed inflammatory background. APN pathology and neurological function were evaluated on the other non-injured sciatic nerve.
Results
TLR4 and its endogenous ligand HMGB1 were highly expressed in L31 mice, in circulating immune cells and in peripheral nerves. Enhanced TLR4 signaling was blocked with TAK 242, a selective TLR4 inhibitor, before and after disease onset. Intraperitoneal administration of TAK 242 not only inhibited monocyte, macrophage and CD8 + T cell activation, but also reduced the release of pro-inflammatory cytokines. TAK 242 protected mice from severe myelin and axonal loss, resulting in a remarkable improvement in mouse motor and sensory functions. TAK 242 was effective in alleviating the disease in both preventive and reversal paradigms.
Conclusion
The study identified the critical contribution of TLR4-mediated macrophage activation in disease course and provided strong evidence to support TLR4 as a useful drug target for treating inflammatory autoimmune neuropathy.
Keywords
Autoimmunity, Inflammation, Demyelination, Macrophages, CD8+ T cells, TLR4, DAMPs
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CURRENT STATUS: Under Revision
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Posted 05 Jan, 2021
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Review #2 received
Received 21 Jan, 2021
Editorial decision: Major Revision
On 21 Jan, 2021
Review #1 received
Received 13 Jan, 2021
Reviewer #2 agreed
On 30 Dec, 2020
Reviewers invited
Invitations sent on 29 Dec, 2020
Reviewer #1 agreed
On 29 Dec, 2020
Editor invited
On 28 Dec, 2020
First submitted
On 27 Dec, 2020
Editor assigned
On 27 Dec, 2020
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Subject Areas
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This preprint is under consideration at Journal of Neuroinflammation. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Inhibition of TLR4 Signaling Protects Mice From Sensory and Motor Dysfunction in an Animal Model of Autoimmune Peripheral Neuropathy
Ji Zhang
McGill University
Corresponding Author
ORCiD: https://orcid.org/0000-0001-8816-9721
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Revision
Version 1
Posted 05 Jan, 2021
No community comments so far
Review #2 received
Received 21 Jan, 2021
Editorial decision: Major Revision
On 21 Jan, 2021
Review #1 received
Received 13 Jan, 2021
Reviewer #2 agreed
On 30 Dec, 2020
Reviewers invited
Invitations sent on 29 Dec, 2020
Reviewer #1 agreed
On 29 Dec, 2020
Editor invited
On 28 Dec, 2020
First submitted
On 27 Dec, 2020
Editor assigned
On 27 Dec, 2020
Submission checks complete
On 27 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurobiology of Disease
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
While the etiology remains elusive, macrophages and T cells in peripheral nerves are considered as effector cells mediating autoimmune peripheral neuropathy (APN), such as Guillain Barre Syndrome. By recognizing both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) signals, TLRs play a central role in the initiation of both innate and adaptive immune responses. In this study, we aimed to understand the involvement of TLR4 in the pathogenesis of APN and explore the potential of TLR4 as a drug target for therapeutic use.
Methods
APN was induced by a partial ligation on one of the sciatic nerves in B7.2 (L31) transgenic mice which possess a predisposed inflammatory background. APN pathology and neurological function were evaluated on the other non-injured sciatic nerve.
Results
TLR4 and its endogenous ligand HMGB1 were highly expressed in L31 mice, in circulating immune cells and in peripheral nerves. Enhanced TLR4 signaling was blocked with TAK 242, a selective TLR4 inhibitor, before and after disease onset. Intraperitoneal administration of TAK 242 not only inhibited monocyte, macrophage and CD8 + T cell activation, but also reduced the release of pro-inflammatory cytokines. TAK 242 protected mice from severe myelin and axonal loss, resulting in a remarkable improvement in mouse motor and sensory functions. TAK 242 was effective in alleviating the disease in both preventive and reversal paradigms.
Conclusion
The study identified the critical contribution of TLR4-mediated macrophage activation in disease course and provided strong evidence to support TLR4 as a useful drug target for treating inflammatory autoimmune neuropathy.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the manuscript can be downloaded and accessed as a PDF.