Sexually Dimorphic Role of Toll-like Receptor 4 (TLR4) in High Molecular Weight Hyaluronan (HMWH)-induced Anti-hyperalgesia.
Sexually Dimorphic Role of Toll-like Receptor 4 (TLR4) in High Molecular Weight Hyaluronan (HMWH)-induced Anti-hyperalgesia.
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DOI：
10.1016/j.jpain.2021.03.152
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Levine JD
中科院分区：
文献类型：
--
作者：
Bonet IJM;Araldi D;Green PG;Levine JD
高分子量透明质酸(HMWH)是细胞外基质的重要组成部分，通过多种受体结合并传递信号，其中包括分化簇44(CD44)和Toll样受体4(TLR4)。我们测试了假设，在炎症的背景下，HMWH在TLR4起作用以减轻痛觉过敏。我们发现，高分子肝素对前列腺素E_2(PGE_2)引起的痛敏的减弱作用可被TLR4拮抗剂(NBP_2-26245)减弱，但仅对雄性和去卵巢雌性大鼠有效。在这项研究中，我们试图评估TLR4信号通路在HMWH诱导的雄性大鼠抗痛敏中的作用。鞘内注射TLR4反义寡核苷酸(ODN)减少伤害性感受器中TLR4的表达，也可减轻HMWH对雄性和去卵巢雌性大鼠的镇痛作用。在卵巢切除的女性中，雌激素替代重建了性腺完整的表型。TLR4第二信使髓系分化因子88(MyD88)的抑制剂可减弱HMWH诱导的抗痛觉过敏，而非MyD88的TLR4信号通路的抑制剂则不能。由于先前研究表明HMWH诱导的抗痛觉过敏也是由CD44介导的，我们评估了TLR4反义ODN和CD44mRNA联合应用的效果。该疗法完全逆转了HMWH诱导的雄性大鼠的抗痛敏反应。我们的结果表明，在HMWH诱导的抗痛敏中，TLR4的性激素依赖、性二态参与，即MyD88依赖。
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.
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DOI：
10.1523/jneurosci.5138-11.2012
发表时间：
2012-02-08
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bogen O;Alessandri-Haber N;Chu C;Gear RW;Levine JD
通讯作者：
Levine JD
影响因子：
3.3
作者：
Ferrari LF;Araldi D;Bogen O;Levine JD
通讯作者：
Levine JD
影响因子：
7.4
作者：
Bonet IJM;Green PG;Levine JD
通讯作者：
Levine JD
影响因子：
4.6
作者：
Ferrari, Luiz F.;Khomula, Eugen V.;Levine, Jon D.
通讯作者：
Levine, Jon D.
影响因子：
5.3
作者：
Bonet, Ivan J. M.;Araldi, Dioneia;Levine, Jon D.
通讯作者：
Levine, Jon D.