Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis

Abstract

Persistent pain after resolution of clinically appreciable signs of arthritis poses a therapeutic challenge and immunosuppressive therapies do not meet this medical need. To investigate this conversion to persistent pain, we utilized the K/BxN serum transfer arthritis model, which has persistent mechanical hypersensitivity despite the resolution of visible inflammation. Toll-like receptor (TLR) 4 has been implicated as a potential therapeutic target in neuropathic and other pain models. We compared the relative courses of serum transfer arthritis and mechanical hypersensitivity in wild type (WT) and Tlr4−/− mice. K/BxN serum transfer induced similar joint swelling and inflammation from days 4–22 in WT and Tlr4−/− mice. Unlike WT mice, Tlr4−/− mice displayed a significant reversal in mechanical hypersensitivity and diminished appearance of glial activation markers after resolution of peripheral inflammation. Intrathecal (IT) delivery of a TLR4 antagonist, LPS-RS (10μg), on days 6, 9, and 12 abrogated the transition to persistent mechanical hypersensitivity in WT arthritic mice, while later administration had no impact. We utilized a lipodomics LC/MS/MS methodology to determine spinal cord profiles of bioactive lipid species following early LPS-RS treatment compared to vehicle treated controls. WT arthritic mice had reduced spinal levels of the anti-inflammatory prostaglandin 15d-PGJ2 on day 6, compared to IT LPS-RS treated mice. Direct IT application of 15d-PGJ2 (0.5μg) on day 6 improved mechanical hypersensitivity in arthritic mice within 15 minutes. Hence, TLR4 signaling altered spinal bioactive lipid profiles in the serum transfer model and played a critical role in the transition from acute to chronic post-inflammatory mechanical hypersensitivity.

Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration

“…It showed potent antiinflammatory and neuroprotective effects in spinal cord cultures, significantly counteracting the effects of TLR4 stimulation by LPS (that is, microglial morphological changes and release of proinflammatory cytokines and motor neuron toxicity). The effects of VB3323 were comparable to those of a wellknown, commercially available TLR4 antagonist, the LPS from RsLPS, which is commonly used to inhibit the TLR4-dependent inflammatory mechanisms (45)(46)(47).…”

Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment

“…By the use of LC-MS-targeted lipidomic approach employed in the present study, the majority of the known inflammatory mediator lipidome can be profiled in a single human biological sample. Recent animal studies have used a similar targeted lipidomics approach to characterize temporal lipid mediator responses during inflammatory models, including experimental arthritis (5,20,32), acute administration of the hyperalgesic/proinflammatory agents carrageenan (12, 31) or LPS (2, 27), and maternal hypercholester- olemia (72). The majority of previous human studies have focused on a select few inflammatory eicosanoids, resulting in a fragmented view of the in vivo lipid mediator dynamics.…”

Pattern recognition receptors in chronic pain: Mechanisms and therapeutic implications

“…The TLR4 deficient mice also showed diminished microglia activation. Intrathecal injection of LPS-RS, a TLR4 specific antagonist naturally produced by Rhodobacter sphaeroides, abrogated the transition to persistent mechanical hypersensitivity (Christianson et al, 2011). In the collagen antibody-induced arthritis (CAIA) model, HMGB1 in the spinal cord played an important role in the development and maintenance of mechanical hypersensitivity via the activation of TLR4.…”