Sexually Dimorphic Role of Toll-like Receptor 4 (TLR4) in High Molecular Weight Hyaluronan (HMWH)-induced Anti-hyperalgesia

Ivan J M Bonet; Dionéia Araldi; Paul G Green; Jon D Levine

doi:10.1016/j.jpain.2021.03.152

Sexually Dimorphic Role of Toll-like Receptor 4 (TLR4) in High Molecular Weight Hyaluronan (HMWH)-induced Anti-hyperalgesia

J Pain. 2021 Oct;22(10):1273-1282. doi: 10.1016/j.jpain.2021.03.152. Epub 2021 Apr 20.

Authors

Ivan J M Bonet¹, Dionéia Araldi¹, Paul G Green², Jon D Levine³

Affiliations

¹ Departments of Medicine and Oral & Maxillofacial Surgery, San Francisco; UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco.
² Departments of Medicine and Oral & Maxillofacial Surgery, San Francisco; UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco; Departments of Preventative and Restorative Dental Sciences, University of California at San Francisco, San Francisco.
³ Departments of Medicine and Oral & Maxillofacial Surgery, San Francisco; UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco; Departments of Medicine, University of California at San Francisco, San Francisco. Electronic address: [email protected].

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.

Keywords: Hyperalgesia; anti-hyperalgesia; high molecular weight hyaluronan (HMWH); hyaluronan; prostaglandin E(2) (PGE(2)); toll-like receptor 4 (TLR4).

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adjuvants, Immunologic
Animals
Dinoprostone / metabolism*
Disease Models, Animal
Female
Hyaluronic Acid / pharmacology*
Hyperalgesia / metabolism*
Male
Molecular Weight
Myeloid Differentiation Factor 88 / pharmacology
Ovariectomy
Rats
Sex Characteristics*
Signal Transduction / drug effects
Signal Transduction / physiology
Toll-Like Receptor 4 / drug effects
Toll-Like Receptor 4 / metabolism*

Substances

Adjuvants, Immunologic
Myd88 protein, rat
Myeloid Differentiation Factor 88
Tlr4 protein, rat
Toll-Like Receptor 4
Hyaluronic Acid
Dinoprostone

Grants and funding

R01 AR075334/AR/NIAMS NIH HHS/United States