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TLR2 Mediates Microglial Activation and Contributes to Central Sensitization in a Recurrent Nitroglycerin-induced Chronic Migraine Model

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Abstract

Central sensitization is an important pathophysiological mechanism underlying chronic migraine (CM). Previous studies have shown that microglial activation and subsequent inflammation in the trigeminal nucleus caudalis (TNC) contribute to central sensitization. Toll-like receptor 2 (TLR2) is a receptor expressed on the membrane of microglia and participates in central sensitization in inflammatory and chronic pain; however, its role in CM is unclear. Therefore, this study investigated TLR2 involvement in CM in detail. Mice treated with recurrent nitroglycerin (NTG) were used as a CM model. Hyperalgesia was assessed using a 50% paw mechanical threshold and a 50% periorbital threshold on a Von Frey filament pain meter. Western blotting and immunofluorescence analyses were used to detect the expression of TLR2, microglia, c-fos and CGRP in TNC. The expression of inflammatory factors (IL-6, IL-1β、 IL-10、TNF-α and IFN-β1) was detected using quantitative real-time polymerase chain reaction (qRT-PCR). A selective TLR2 antagonist (C29) was systematically administered to observe its effect on hyperalgesia, microglia activation and the expression of c-fos, CGRP and inflammatory factors. Recurrent administration of NTG resulted in acute and chronic hypersensitivity, accompanied by upregulation of TLR2 expression and microglial activation in TNC. C29 partially inhibited pain hypersensitivity. C29 suppressed microglial activation induced by NTG administration. Inhibition of TLR2 reduced the expression of c-fos and CGRP in TNC after NTG treatment. C29 inhibited the expression of inflammatory mediators in TNC. These data showed that microglial TLR2 plays a critical role in the pathogenesis of CM by regulating microglial activation in TNC.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CM:

Chronic migraine

TNC:

Trigeminal nucleus caudalis

TLRs:

Toll-like receptors

TLR2:

Toll-like receptor 2

TLR3:

Toll-like receptor 3

TLR4:

Toll-like receptor 4

CSD:

Cortical Spreading Depression

NTG:

Nitroglycerin

VEH:

Vehicle

IL-6:

Interleukin-6

IL-1β:

Interleukin-1β

IL-10:

Interleukin-10

TNF-α:

Tumor necrosis factor-α

IFN-β1:

Interferon-β1

PBS:

Phosphate-buffered saline

IF:

Immunofluorescence

PFA:

Paraformaldehyde

OCT:

Optimal cutting temperature compound

DAPI:

4’,6-Diamidino-2-phenylindole

qRT-PCR:

Quantitative real-time polymerase chain reaction

CGRP:

Calcitonin gene related peptide

CSF1:

Colony-stimulating factor 1

NF-κB:

Nuclearfactor-κB

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Acknowledgments

We sincerely thank Academician Wang Longde for his technical guidance in this study. In addition, we are sincerely grateful to all the staff of Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences.

Funding

This work was supported by the Gansu Provincial Neurology Clinical Medical Research Center (Grant numbers: 20JR10FA663), Cuiying Technology Innovation Program of Lanzhou University Second Hospital (Grant numbers: CY2022-QN-B03) and Academician Wang Longde Expert Workstation of Lanzhou University Second Hospital.

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  1. Xuejiao Liu, Wenping Yang, Chenlu Zhu contributed equally to this work as co-first authors.

  2. Zhiyan Liu and Zhaoming Ge contributed equally to this work as co-corresponding authors.

Authors and Affiliations

  1. Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China

    Xuejiao Liu, Chenlu Zhu, Songtang Sun, Bin Yang, Shouyi Wu, Zhiyan Liu & Zhaoming Ge

  2. State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China

    Wenping Yang

  3. Expert Workstation of Academician Wang Longde, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China

    Longde Wang

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Contributions

XJL, ZMG and ZYL contributed to the work design. Animal behavior experiments were performed by XJL, STS, BY and SYW. Molecular biology experiments were performed by XJL, WPY and CLZ. ZYL and WPY performed the statistical analysis. LXJ wrote and completed the manuscript. ZMG, LDW, ZYL and CLZ revised the manuscript. All authors read and approved the final manuscript and agreed to take responsibility for all aspects of the work.

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Correspondence to Zhiyan Liu or Zhaoming Ge.

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Liu, X., Yang, W., Zhu, C. et al. TLR2 Mediates Microglial Activation and Contributes to Central Sensitization in a Recurrent Nitroglycerin-induced Chronic Migraine Model. Mol Neurobiol 61, 3697–3714 (2024). https://doi.org/10.1007/s12035-023-03781-2

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