Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells
Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells
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DOI：
10.1073/pnas.1410700111
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发表时间：
2014-10-28
影响因子：
11.1
通讯作者：
Girard, Jean-Philippe
中科院分区：
文献类型：
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作者：
Lefrancais, Emma;Duval, Anais;Girard, Jean-Philippe
白细胞介素-33（IL-33）是来自IL-1家族的警报细胞因子。IL-33激活许多表达白细胞介素1受体样1（IL 1 RL 1）受体ST 2的免疫细胞类型，包括2型先天性淋巴样细胞（ILC 2，天然辅助细胞，核细胞），2型先天性免疫应答和过敏性气道炎症期间IL-5和IL-13的主要生产者。IL-33可能在哮喘中发挥关键作用，因为IL-33和ST 2/IL 1 RL 1基因在大规模全基因组关联研究中已被重复鉴定为主要易感基因座。因此，迫切需要更好地了解调节IL-33活性的机制。在这里，我们研究了肥大细胞的作用，过敏性疾病中的关键效应细胞，已知在体内与ILC 2相互作用。我们发现由活化的肥大细胞分泌的丝氨酸蛋白酶（糜酶和类胰蛋白酶）产生对ILC 2具有有效活性的成熟形式的IL-33。由肥大细胞蛋白酶产生的主要形式IL-33（95-270）、IL-33（107-270）和IL-33（109-270）在离体活化ILC 2方面比全长人IL-33（1-270）强30倍。它们在体内诱导ILC 2和嗜酸性粒细胞的强烈扩增，与IL-5和IL-13浓度升高相关。鼠IL-33也被肥大细胞类胰蛋白酶切割，类胰蛋白酶抑制剂减少体内IL-33依赖性过敏性气道炎症。我们的研究鉴定了IL-33的中央切割/激活结构域（氨基酸66-111）作为该蛋白的重要功能结构域，并表明通过肥大细胞和其他炎性蛋白酶干扰IL-33的切割和激活可能有助于减少过敏性哮喘和其他炎性疾病中IL-33介导的反应。
Interleukin-33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 activates many immune cell types expressing the interleukin 1 receptor-like 1 (IL1RL1) receptor ST2, including group-2 innate lymphoid cells (ILC2s, natural helper cells, nuocytes), the major producers of IL-5 and IL-13 during type-2 innate immune responses and allergic airway inflammation. IL-33 is likely to play a critical role in asthma because the IL33 and ST2/IL1RL1 genes have been reproducibly identified as major susceptibility loci in large-scale genome-wide association studies. A better understanding of the mechanisms regulating IL-33 activity is thus urgently needed. Here, we investigated the role of mast cells, critical effector cells in allergic disorders, known to interact with ILC2s in vivo. We found that serine proteases secreted by activated mast cells (chymase and tryptase) generate mature forms of IL-33 with potent activity on ILC2s. The major forms produced by mast cell proteases, IL-33(95-270), IL-33(107-270), and IL-33(109-270), were 30-fold more potent than full-length human IL-33(1-270) for activation of ILC2s ex vivo. They induced a strong expansion of ILC2s and eosinophils in vivo, associated with elevated concentrations of IL-5 and IL-13. Murine IL33 is also cleaved by mast cell tryptase, and a tryptase inhibitor reduced IL-33-dependent allergic airway inflammation in vivo. Our study identifies the central cleavage/activation domain of IL-33 (amino acids 66-111) as an important functional domain of the protein and suggests that interference with IL-33 cleavage and activation by mast cell and other inflammatory proteases could be useful to reduce IL-33-mediated responses in allergic asthma and other inflammatory diseases.