IL-33在雌性肥大细胞和中性粒细胞中诱导更强的反应：JNK信号通路的作用
2026/07/31
摘要
引言：过敏性疾病呈现出显著的性别差异，成年女性患过敏性哮喘、特应性皮炎、食物过敏和慢性荨麻疹的几率更高。这种女性主导的现象可能与炎症信号传导的差异有关。
方法：我们使用原代小鼠肥大细胞、中性粒细胞和嗜酸性粒细胞，以及两种白细胞介素-33（IL-33）诱导炎症的小鼠模型，来测定雄性和雌性对IL-33的反应。
结果：我们发现，与雄性相比，无论是在体外还是体内，与过敏相关的细胞因子IL-33都会引发雌性肥大细胞和中性粒细胞更强的反应。雌性更强的反应并不是因为雌性细胞中IL-33受体的表达增加或敏感性增强。相反，我们注意到IL-33会选择性激活雌性细胞中的JNK信号通路。雄性和雌性肥大细胞在响应IL-33产生炎症细胞因子时，都需要ERK、p38、NF-κB和AP-1信号通路。然而，抑制JNK信号通路会选择性降低雌性肥大细胞中IL-33介导的细胞因子产生。在一个依赖肥大细胞的IL-33诱导腹膜炎的小鼠模型中，性腺切除消除了中性粒细胞流入反应的性别差异。然而，即使在缺乏性器官的小鼠中，雌性小鼠的血浆IL-13水平仍然较高。
讨论：这些数据表明，IL-33诱导以雌性为主导的肥大细胞和中性粒细胞反应，部分是通过雌性选择性的JNK信号传导实现的。
IL-33 induces stronger responses in female mast cells and neutrophils: a role for the JNK pathway
Sydney Ann Kee, Tania D Maldonado, John M Ching, Catherine Nelson, Zakaria Y Hussain, An Z Yao, Aditya Kotha, Hadi Hamze, Jason R Burchett, John J Ryan
Abstract
Introduction: Allergic diseases exhibit considerable sex-based variations, with greater incidence of allergic asthma, atopic dermatitis, food allergy, and chronic urticaria among adult females. This female dominance may be explained by differences in inflammatory signaling.
Methods: We used primary mouse mast cells, neutrophils, and eosinophils as well as two mouse models of IL-33-induced inflammation to measure male and female responses to IL-33.
Results: We show that the allergy-associated cytokine IL-33 elicits stronger responses from female mast cells and neutrophils compared to males, both in vitro and in vivo. The greater female response was not due to increased expression or sensitivity of the IL-33 receptor in female cells. Instead, we noted female-selective activation of the JNK pathway in response to IL-33. Male and female mast cells both required the ERK, p38, NF-kB, and AP-1 pathways to produce inflammatory cytokines in response to IL-33. However, inhibiting the JNK pathway selectively reduced IL-33-mediated cytokine production in female mast cells. A mast cell-dependent model of IL-33-induced peritonitis showed that gonadectomy ablated sexual dimorphism in the neutrophil influx response. However, plasma IL-13 levels remained higher in females even among mice lacking sex organs.
Discussion: These data show that IL-33 induces female-dominant mast cell and neutrophil responses, partly via female-selective JNK signaling.
引言：过敏性疾病呈现出显著的性别差异，成年女性患过敏性哮喘、特应性皮炎、食物过敏和慢性荨麻疹的几率更高。这种女性主导的现象可能与炎症信号传导的差异有关。
方法：我们使用原代小鼠肥大细胞、中性粒细胞和嗜酸性粒细胞，以及两种白细胞介素-33（IL-33）诱导炎症的小鼠模型，来测定雄性和雌性对IL-33的反应。
结果：我们发现，与雄性相比，无论是在体外还是体内，与过敏相关的细胞因子IL-33都会引发雌性肥大细胞和中性粒细胞更强的反应。雌性更强的反应并不是因为雌性细胞中IL-33受体的表达增加或敏感性增强。相反，我们注意到IL-33会选择性激活雌性细胞中的JNK信号通路。雄性和雌性肥大细胞在响应IL-33产生炎症细胞因子时，都需要ERK、p38、NF-κB和AP-1信号通路。然而，抑制JNK信号通路会选择性降低雌性肥大细胞中IL-33介导的细胞因子产生。在一个依赖肥大细胞的IL-33诱导腹膜炎的小鼠模型中，性腺切除消除了中性粒细胞流入反应的性别差异。然而，即使在缺乏性器官的小鼠中，雌性小鼠的血浆IL-13水平仍然较高。
讨论：这些数据表明，IL-33诱导以雌性为主导的肥大细胞和中性粒细胞反应，部分是通过雌性选择性的JNK信号传导实现的。
（中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校）
（Front Immunol. 2026 Jul 7:17:1813530. doi: 10.3389/fimmu.2026.1813530.）
（Front Immunol. 2026 Jul 7:17:1813530. doi: 10.3389/fimmu.2026.1813530.）
IL-33 induces stronger responses in female mast cells and neutrophils: a role for the JNK pathway
Sydney Ann Kee, Tania D Maldonado, John M Ching, Catherine Nelson, Zakaria Y Hussain, An Z Yao, Aditya Kotha, Hadi Hamze, Jason R Burchett, John J Ryan
Abstract
Introduction: Allergic diseases exhibit considerable sex-based variations, with greater incidence of allergic asthma, atopic dermatitis, food allergy, and chronic urticaria among adult females. This female dominance may be explained by differences in inflammatory signaling.
Methods: We used primary mouse mast cells, neutrophils, and eosinophils as well as two mouse models of IL-33-induced inflammation to measure male and female responses to IL-33.
Results: We show that the allergy-associated cytokine IL-33 elicits stronger responses from female mast cells and neutrophils compared to males, both in vitro and in vivo. The greater female response was not due to increased expression or sensitivity of the IL-33 receptor in female cells. Instead, we noted female-selective activation of the JNK pathway in response to IL-33. Male and female mast cells both required the ERK, p38, NF-kB, and AP-1 pathways to produce inflammatory cytokines in response to IL-33. However, inhibiting the JNK pathway selectively reduced IL-33-mediated cytokine production in female mast cells. A mast cell-dependent model of IL-33-induced peritonitis showed that gonadectomy ablated sexual dimorphism in the neutrophil influx response. However, plasma IL-13 levels remained higher in females even among mice lacking sex organs.
Discussion: These data show that IL-33 induces female-dominant mast cell and neutrophil responses, partly via female-selective JNK signaling.
