Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice

Journal of Neuroinflammation

Tony L Yaksh²  Maripat Corr¹  Kelly Eddinger²  Jonathan Cheung²  Jennifer A Stokes² 

[1] Division of Rheumatology, Allergy and Immunology, University of California, 9500 Gilman Dr. MC 0663, La Jolla, San Diego, CA 92093-0663, USA;Department of Anesthesiology, University of California, 9500 Gilman Dr. MC 0818, La Jolla, San Diego, CA 92093-0818, USA

关键词: TRIF;    Toll-like receptors;    Spinal nerve ligation;    MyD88;    Interferon-beta;    Hyperalgesia;    Allodynia;   

Others  :  834602
DOI  :  10.1186/1742-2094-10-148

 received in 2013-03-20, accepted in 2013-11-18,  发布年份 2013

【 摘 要 】

Background

Spinal Toll-like receptors (TLRs) and signaling intermediaries have been implicated in persistent pain states. We examined the roles of two major TLR signaling pathways and selected TLRs in a mononeuropathic allodynia.

Methods

L5 spinal nerve ligation (SNL) was performed in wild type (WT, C57BL/6) male and female mice and in male Tlr2^-/-Tlr3^-/-, Tlr4^-/-, Tlr5^-/-, Myd88^-/-, Trif^lps2, Myd88/Trif^lps2, Tnf^-/-, and Ifnar1^-/- mice. We also examined L5 ligation in Tlr4^-/- female mice. We examined tactile allodynia using von Frey hairs. Iba-1 (microglia) and GFAP (astrocytes) were assessed in spinal cords by immunostaining. Tactile thresholds were analyzed by 1- and 2-way ANOVA and the Bonferroni post hoc test was used.

Results

In WT male and female mice, SNL lesions resulted in a persistent and robust ipsilateral, tactile allodynia. In males with TLR2, 3, 4, or 5 deficiencies, tactile allodynia was significantly, but incompletely, reversed (approximately 50%) as compared to WT. This effect was not seen in female Tlr4^-/- mice. Increases in ipsilateral lumbar Iba-1 and GFAP were seen in mutant and WT mice. Mice deficient in MyD88, or MyD88 and TRIF, showed an approximately 50% reduction in withdrawal thresholds and reduced ipsilateral Iba-1. In contrast, TRIF and interferon receptor null mice developed a profound ipsilateral and contralateral tactile allodynia. In lumbar sections of the spinal cords, we observed a greater increase in Iba-1 immunoreactivity in the TRIF-signaling deficient mice as compared to WT, but no significant increase in GFAP. Removing MyD88 abrogated the contralateral allodynia in the TRIF signaling-deficient mice. Conversely, IFNβ, released downstream to TRIF signaling, administered intrathecally, temporarily reversed the tactile allodynia.

Conclusions

These observations suggest a critical role for the MyD88 pathway in initiating neuropathic pain, but a distinct role for the TRIF pathway and interferon in regulating neuropathic pain phenotypes in male mice.

【 授权许可】

   
2013 Stokes et al.; licensee BioMed Central Ltd.

【 图 表 】

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