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 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.
J Pain. 2021 Oct;22(10):1273-1282. doi: 10.1016/j.jpain.2021.03.152. Epub 2021 Apr 20.
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 E (PGE)-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.
高分子量透明质酸（HMWH）是细胞外基质的主要成分之一，可与多种受体结合并发出信号，包括 CD44 和 Toll 样受体 4（TLR4）。我们验证了一个假说，即在炎症环境下，HMWH 通过 TLR4 发挥作用，从而减轻痛觉过敏。我们发现，TLR4 拮抗剂（NBP2-26245）削弱了 HMWH 对前列腺素 E（PGE）诱导的痛觉过敏的抑制作用，但仅在雄性和去卵巢雌性大鼠中如此。在本研究中，我们旨在评估 TLR4 信号通路在 HMWH 诱导雄性大鼠抗痛觉过敏中的作用。鞘内给予 TLR4 反义寡核苷酸（ODN）降低伤害感受器中 TLR4 的表达，也削弱了 HMWH 在雄性和去卵巢雌性大鼠中的抗痛觉过敏作用。在去卵巢雌性大鼠中给予雌激素替代物，可重建正常的性腺状态。髓样分化因子 88（MyD88）抑制剂（TLR4 的第二信使）的给药削弱了 HMWH 诱导的抗痛觉过敏作用，而 MyD88 非依赖性 TLR4 信号通路抑制剂则没有。因为先前已经表明 HMWH 诱导的抗痛觉过敏作用部分也由 CD44 介导，所以我们评估了 TLR4 和 CD44 mRNA 反义 ODN 联合给药的效果。这种治疗方法完全逆转了雄性大鼠中 HMWH 诱导的抗痛觉过敏作用。我们的结果表明，TLR4 在 HMWH 诱导的抗痛觉过敏作用中存在性激素依赖性的性别二态性和 MyD88 依赖性，这为治疗炎症性疼痛提供了一个新的分子靶点。
HMWH 诱导的抗痛觉过敏作用中 TLR4 的作用是一种性别二态性、TLR4 依赖性的炎症性痛觉过敏抑制作用，为治疗炎症性疼痛提供了一个新的分子靶点。
