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Rifampin inhibits Toll-like receptor 4 signaling by targeting myeloid differentiation protein 2 and attenuates neuropathic pain.

ABSTRACT: Rifampin has been used for the treatment of bacterial infections for many years. Clinically, rifampin has been found to possess immunomodulatory effects. However, the molecular target responsible for the immunosuppressive effects of rifampin is not known. Herein, we show that rifampin binds to myeloid differentiation protein 2 (MD-2), the key coreceptor for innate immune TLR4. Rifampin blocked TLR4 signaling induced by LPS, including NF-?B activation and the overproduction of proinflammatory mediators nitric oxide, interleukin 1?, and tumor necrosis factor ? in mouse microglia BV-2 cells and macrophage RAW 264.7 cells. Rifampin's inhibition of TLR4 signaling was also observed in immunocompetent rat primary macrophage, microglia, and astrocytes. Further, we show that rifampin (75 or 100 mg/kg b.i.d. for 3 d, intraperitoneal) suppressed allodynia induced by chronic constriction injury of the sciatic nerve and suppressed nerve injury-induced activation of microglia. Our findings indicate that MD-2 is a important target of rifampin in its inhibition of innate immune function and contributes to its clinically observed immune-suppressive effect. The results also suggest that rifampin may be repositioned as an agent for the treatment of neuropathic pain.

SUBMITTER: Wang X

PROVIDER: S-EPMC3688759 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Rifampin inhibits Toll-like receptor 4 signaling by targeting myeloid differentiation protein 2 and attenuates neuropathic pain.

Wang Xiaohui X Grace Peter M PM Pham Michael N MN Cheng Kui K Strand Keith A KA Smith Christina C Li Jing J Watkins Linda R LR Yin Hang H

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20130408 7

Rifampin has been used for the treatment of bacterial infections for many years. Clinically, rifampin has been found to possess immunomodulatory effects. However, the molecular target responsible for the immunosuppressive effects of rifampin is not known. Herein, we show that rifampin binds to myeloid differentiation protein 2 (MD-2), the key coreceptor for innate immune TLR4. Rifampin blocked TLR4 signaling induced by LPS, including NF-κB activation and the overproduction of proinflammatory med ...[more]

PMID: 23568774

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Project description: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-/-, Triflps2, Myd88/Triflps2, 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, IFN?, 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.

Dataset Information

Rifampin inhibits Toll-like receptor 4 signaling by targeting myeloid differentiation protein 2 and attenuates neuropathic pain.

Publications

Rifampin inhibits Toll-like receptor 4 signaling by targeting myeloid differentiation protein 2 and attenuates neuropathic pain.

Similar Datasets

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