Toll-like receptor 2 and 4 antagonism for the treatment of experimental autoimmune encephalomyelitis (EAE)-related pain

Andrew J. Kwilasz*, Suzanne M. Green Fulgham, Julissa Chante Duran-Malle, Anouk E.W. Schrama, Eric H. Mitten, Laurel S. Todd, Hardik P. Patel, Tracey A. Larson, Madison A. Clements, Kevin M. Harris, Scott T. Litwiler, Lewis O. Harvey, Steven F. Maier, Raymond A. Chavez, Kenner C. Rice, Anne Marie Van Dam, Linda R. Watkins

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Neuropathic pain is a major symptom of multiple sclerosis (MS) with up to 92% of patients reporting bodily pain, and 85% reporting pain severe enough to cause functional disability. None of the available therapeutics target MS pain. Toll-like receptors 2 and 4 (TLR2/TLR4) have emerged as targets for treating a wide array of autoimmune disorders, including MS, as well as having demonstrated success at suppressing pain in diverse animal models. The current series of studies tested systemic TLR2/TLR4 antagonists in males and females in a low-dose Myelin oligodendrocyte glycoprotein (MOG) experimental autoimmune encephalomyelitis (EAE) model, with reduced motor dysfunction to allow unconfounded testing of allodynia through 50+ days post-MOG. The data demonstrated that blocking TLR2/TLR4 suppressed EAE-related pain, equally in males and females; upregulation of dorsal spinal cord proinflammatory gene expression for TLR2, TLR4, NLRP3, interleukin-1β, IkBα, TNF-α and interleukin-17; and upregulation of dorsal spinal cord expression of glial immunoreactivity markers. In support of these results, intrathecal interleukin-1 receptor antagonist reversed EAE-induced allodynia, both early and late after EAE induction. In contrast, blocking TLR2/TLR4 did not suppress EAE-induced motor disturbances induced by a higher MOG dose. These data suggest that blocking TLR2/TLR4 prevents the production of proinflammatory factors involved in low dose EAE pathology. Moreover, in this EAE model, TLR2/TLR4 antagonists were highly effective in reducing pain, whereas motor impairment, as seen in high dose MOG EAE, is not affected.

Original languageEnglish
Pages (from-to)80-95
Number of pages16
JournalBrain, Behavior, and Immunity
Volume93
DOIs
Publication statusPublished - Mar 2021

Cite this