The Macrophage IL-23/IL-17A Pathway: A New Neuro-Immune Mechanism in Female Mechanical Pain
The Macrophage IL-23/IL-17A Pathway: A New Neuro-Immune Mechanism in Female Mechanical Pain
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巨噬细胞 IL-23/IL-17A 通路：女性机械性疼痛的新神经免疫机制
DOI：
10.1007/s12264-021-00797-3
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Zhou Lijun
中科院分区：
文献类型：
--
作者：
Tan Zhi;Lin Zhen-Jia;Wu Long-Jun;Zhou Lijun
大量临床证据表明，许多慢性疼痛综合征的患病率和严重程度在性别之间存在差异，女性比男性更明显[1]。但大多数关于慢性疼痛机制的临床前研究主要是在雄性动物中进行的。一般认为，外周和中枢神经系统中的炎症反应对慢性疼痛至关重要[2，3]。鉴于性别二态性影响各种疾病的免疫力[4]，最近的研究表明，脊髓小胶质细胞或背根神经节（DRG）巨噬细胞选择性调节雄性小鼠的神经性疼痛[1]。然而，女性慢性疼痛发生率高于男性的具体分子机制仍不清楚。白细胞介素-23（IL-23）/IL-17轴对多种炎症性疾病（如银屑病和关节炎）的进展至关重要[5]，这些疾病在女性中更为普遍。根据这一想法，RR Ji小组最近的一项研究对机械疼痛状态下巨噬细胞-感觉神经元串扰引起的性别二态性中的IL-23/IL-17轴提供了新的见解[6]（图1）。促炎细胞因子IL-23首次被报道在关节炎和炎性疼痛进展和疾病中具有T细胞非依赖性功能[7]，但没有性别差异。在这里，在Ji小组的新研究中，作者设计了一系列优雅的实验来阐明IL-23在性别二态性疼痛中的作用。首先，足底注射IL-23剂量依赖性地诱导机械性异常性疼痛，特异性地通过IL-23受体（IL-23Rs）仅在未处理的雌性小鼠中，而不是在雄性小鼠中。第二，IL-23/IL-23R轴是产生女性特异性机械性异常性疼痛（神经性疼痛）和自发性疼痛（炎性疼痛）所必需的。第三，用化疗剂紫杉醇治疗后，体内血清和DRG或体外腹腔巨噬细胞中的IL-23增加。更重要的是，IL-23通过巨噬细胞的自分泌和旁分泌作用以及间接激活C纤维伤害感受器在雌性中发挥作用。这些结果共同表明，在涉及巨噬细胞和伤害感受器的多个细胞水平上，IL-23在机械性疼痛发展中的性别二态性作用。为了解决这个问题，Ji的研究集中在IL-17上，IL-17是受IL-23调节的重要效应分子之一，在炎症中显示出性别二态性。IL-17通过T细胞依赖性或非依赖性机制（包括神经元-胶质细胞相互作用、中枢致敏和外周致敏）在驱动慢性疼痛中发挥关键作用[8]，但在该作用中未显示性别差异。在这里，Luo et al. [6]报道，在紫杉醇处理后，雄性和雌性腹腔巨噬细胞中的IL-17A（IL-17的一种亚型）均增加，但在IL-23刺激后，雌性中的IL-17A更高。足底IL-17 A仅在高剂量（100 ng）下诱导雄性动物的机械性疼痛，但在低剂量（1和10 ng）下诱导雌性动物的机械性疼痛，这与巨噬细胞或IL-23无关。此外，阻断IL-17 A/IL-17 R信号传导抑制了雌性中IL-23诱导的疼痛。有趣的是，通过使用Ca2+成像和全细胞膜片钳记录，作者发现低剂量的IL-
Considerable clinical evidence has demonstratedthat the prevalence and severity of many chronic pain syndromes differ across sex, and are more predominant in women than in men [1]. But most preclinical research on chronic pain mechanisms has been performed primarily in male animals. It is generally understood that inflammatory responses in the peripheral and central nervous systems are critical for chronic pain [2, 3]. Given that sex dimorphism influences immunity in various diseases [4], recent studies have revealed that spinal microglia or dorsal root ganglion (DRG) macrophages regulate neuropathic pain selectively in male mice [1]. However, the specific molecular mechanism underlying the greater occurrence of chronic pain among females than males remains unknown. The interleukin-23 (IL-23)/IL-17 axis is crucial to the progression of multiple inflammatory diseases (such as psoriasis and arthritis)[5], which are more prevalent among females. In line with this idea, a recent study from the RR Ji group provided new insights into the IL-23/IL-17 axis in sex dimorphism arising from macrophage-sensory neuron crosstalk in mechanical pain states [6](Fig. 1). The pro-inflammatory cytokine IL-23 was first reported to have a T cell-independent function in arthritic and inflammatory pain progression and disease [7], but without gender disparity. Here, in the new study by the Ji group [6], the authors designed an elegant series of experiments to elucidate the role of IL-23 in pain in a sex-dimorphic manner. First, intraplantar injections of IL-23 dose-dependently induced mechanical allodynia specifically through IL-23 receptors (IL-23Rs) only in naıve female mice and not in males. Second, the IL-23/IL-23R axis was required for generating female-specific mechanical allodynia (neuropathic pain) and spontaneous pain (inflammatory pain). Third, IL-23 was increased in the serum and DRGs in vivo or peritoneal macrophages in vitro after treatment with the chemotherapeutic agent paclitaxel. More importantly, IL-23 exerted its effects in females via the autocrine and paracrine actions of macrophages and indirectly activating C-fiber nociceptors. These results collectively demonstrated a sex-dimorphic role of IL-23 in mechanical pain development at multiple cellular levels involving macrophages and nociceptors.The next question is how IL-23 induces mechanical pain in a sex-specific fashion. To address this question, Ji’s study focused on IL-17, which is one of the important effector molecules regulated by IL-23 and displays sex dimorphism in inflammation. IL-17 plays a critical role in driving chronic pain via T cell-dependent or-independent mechanisms, including neuron-glial interactions, central sensitization, and peripheral sensitization [8], but no gender differences were shown in the effect. Here, Luo et al.[6] reported that IL-17A (a subtype of IL-17) was increased in both male and female peritoneal macrophages after paclitaxel treatment, but was greater in females after IL-23 stimulation. Intraplantar IL-17A induced mechanical pain in males only at a high dose (100 ng) but in females at low doses (1 and 10 ng), which was independent of macrophages or IL-23. Moreover, blocking IL-17A/IL-17R signaling suppressed IL-23-induced pain in females. Interestingly, by using Ca2+ imaging and whole-cell patchclamp recording, the authors found that a low dose of IL-
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影响因子：
6.5
作者：
Nattkemper, Leigh A.;Tey, Hong Liang;Yosipovitch, Gil
通讯作者：
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影响因子：
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作者：
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作者：
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影响因子：
16.6
作者：
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影响因子：
16.2
作者：
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