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

Abstract

BackgroundSpinal 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.MethodsL5 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.ResultsIn 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.ConclusionsThese 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.

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“…It should be noted that the role of TLR4 in OIH has been challenged (50,51), although these data do not preclude a role for this receptor in morphine-induced persistent sensitization. Furthermore, TLR4 is posited to exclusively regulate male pain behaviors (26,52). However, ongoing studies indicate that morphine-induced persistent sensitization also occurs in female rodents.…”

A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling

“…(18), parasitic infections caused by Trypanosoma and Leishmania spp. (18), chronic viral infection (8,19), and in the transmission of neuropathic pain (20). It has been hypothesized that a targeted reduction in IFN-␤-IFNAR1 signals may be sufficient to protect the host against the lethality of experimental sepsis (21).…”

The Bacterial Component Flagellin Induces Anti-Sepsis Protection Through TLR-5, IL-1RN and VCAN During Polymicrobial Sepsis in Mice

“…Eventually, the transcription factor NF-κB dissociates from inhibitor kappa B (I-κB) and translocates into the nucleus, where it controls the transcription of inflammatory mediators [15,16]. Moreover, different toll-like receptors have been shown to possess different functions.…”