Journal article
Sexually Dimorphic Role of Toll-like Receptor 4 (TLR4) in High Molecular Weight Hyaluronan (HMWH)-induced Anti-hyperalgesia
The journal of pain, Vol.22(10), pp.1273-1282
10/01/2021
DOI: 10.1016/j.jpain.2021.03.152
PMID: 33892155
Abstract
High molecular weight hyaluronan (HMWH), a prominent component of the extracellular matrix binds to and signals via multiple receptors, including cluster of differentiation 44 (CD44) and toll-like receptor 4 (TLR4). We tested the hypothesis that, in the setting of inflammation, HMWH acts at TLR4 to attenuate hyperalgesia. We found that the attenuation of prostaglandin E2 (PGE2)-induced hyperalgesia by HMWH was attenuated by a TLR4 antagonist (NBP2-26245), but only in male and ovariectomized female rats. In this study we sought to evaluated the role of the TLR4 signaling pathway in anti-hyperalgesia induced by HMWH in male rats. Decreasing expression of TLR4 in nociceptors, by intrathecal administration of an oligodeoxynucleotide (ODN) antisense to TLR4 mRNA, also attenuated HMWH-induced anti-hyperalgesia, in male and ovariectomized female rats. Estrogen replacement in ovariectomized females reconstituted the gonad-intact phenotype. The administration of an inhibitor of myeloid differentiation factor 88 (MyD88), a TLR4 second messenger, attenuated HMWH-induced anti-hyperalgesia, while an inhibitor of the MyD88-independent TLR4 signaling pathway did not. Since it has previously been shown that HMWH-induced anti-hyperalgesia is also mediated, in part by CD44 we evaluated the effect of the combination of ODN antisense to TLR4 and CD44 mRNA. This treatment completely reversed HMWH-induced anti-hyperalgesia in male rats. Our results demonstrate a sex hormone-dependent, sexually dimorphic involvement of TLR4 in HMWH-induced anti-hyperalgesia, that is MyD88 dependent.
Perspective: The role of TLR4 in anti-hyperalgesia induced by HMWH is a sexually dimorphic, TLR4 dependent inhibition of inflammatory hyperalgesia that provides a novel molecular target for the treatment of inflammatory pain. (C) 2021 by United States Association for the Study of Pain, Inc.
Details
- Title: Subtitle
- Sexually Dimorphic Role of Toll-like Receptor 4 (TLR4) in High Molecular Weight Hyaluronan (HMWH)-induced Anti-hyperalgesia
- Creators
- Ivan J. M. Bonet - University of California, San FranciscoDioneia Araldi - University of California, San FranciscoPaul G. Green - University of California, San FranciscoJon D. Levine - University of California, San Francisco
- Resource Type
- Journal article
- Publication Details
- The journal of pain, Vol.22(10), pp.1273-1282
- DOI
- 10.1016/j.jpain.2021.03.152
- PMID
- 33892155
- ISSN
- 1526-5900
- eISSN
- 1528-8447
- Publisher
- Elsevier
- Number of pages
- 10
- Grant note
- AR075334 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 10/01/2021
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9985177948802771
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