TY - JOUR
T1 - Toll-like receptor 2 and 4 antagonism for the treatment of experimental autoimmune encephalomyelitis (EAE)-related pain
AU - Kwilasz, Andrew J.
AU - Green Fulgham, Suzanne M.
AU - Duran-Malle, Julissa Chante
AU - Schrama, Anouk E.W.
AU - Mitten, Eric H.
AU - Todd, Laurel S.
AU - Patel, Hardik P.
AU - Larson, Tracey A.
AU - Clements, Madison A.
AU - Harris, Kevin M.
AU - Litwiler, Scott T.
AU - Harvey, Lewis O.
AU - Maier, Steven F.
AU - Chavez, Raymond A.
AU - Rice, Kenner C.
AU - Van Dam, Anne Marie
AU - Watkins, Linda R.
N1 - Funding Information: This work was supported in part by grants from the National Institute of Neurological Disorders and Stroke ( R01NS097313 ); the University of Colorado Biological Sciences Initiative; and by the intramural Research programs of the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism , National Institute on Health . Publisher Copyright: © 2020 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - Allodynia
KW - C57Bl6/J mice
KW - Dark Agouti rats
KW - Motor disturbances
KW - Myelin oligodendrocyte glycoprotein (MOG)
KW - Sex differences
UR - http://www.scopus.com/inward/record.url?scp=85099139558&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bbi.2020.12.016
DO - https://doi.org/10.1016/j.bbi.2020.12.016
M3 - Article
C2 - 33358978
SN - 0889-1591
VL - 93
SP - 80
EP - 95
JO - Brain, behavior, and immunity
JF - Brain, behavior, and immunity
ER -