Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Ireland.
Front Immunol. 2022 Jun 30;13:879029. doi: 10.3389/fimmu.2022.879029. eCollection 2022.
Inflammation driven by environmental allergens is an important source of morbidity in diseases such as asthma and eczema. How common allergens promote inflammation is still poorly understood, but previous studies have implicated the protease activity associated with many allergens as an important component of the pro-inflammatory properties of these agents. The IL-1 family cytokine, IL-33, has recently been shown to undergo processing and activation by proteases associated with multiple common allergens. However, it remains unclear whether the sensing of exogenous protease activity-as a proxy for the detection of invasive microbes, allergens and parasitic worms-is a general property of IL-1 family cytokines. In common with the majority of IL-1 family members, cytokines within the IL-36 sub-family (IL-36α, IL-36β and IL-36γ) are expressed as inactive precursors that require proteolysis within their N-termini for activation. Here we show that proteases associated with multiple common allergens of plant, insect, fungal and bacterial origin (including: , ragweed, rye, house dust mite, cockroach and ) are capable of processing and activating IL-36 family cytokines, with IL-36β being particularly susceptible to activation by multiple allergens. Furthermore, extracts from several allergens also processed and enhanced IL-1α activity. This suggests that multiple IL-1 family cytokines may serve as sentinels for exogenous proteases, coupling detection of such activity to unleashing the pro-inflammatory activity of these cytokines. Taken together with previous data on the diversity of proteases capable of activating IL-1 family cytokines, this suggests that members of this cytokine family may function as 'activity recognition receptors' for aberrant protease activity associated with infection, tissue injury or programmed necrosis.
由环境过敏原引起的炎症是哮喘和湿疹等疾病发病的重要原因。目前尚不清楚常见过敏原如何促进炎症，但先前的研究表明，与许多过敏原相关的蛋白酶活性是这些物质促炎特性的重要组成部分。IL-1 家族细胞因子 IL-33 最近被证明可被与多种常见过敏原相关的蛋白酶进行加工和激活。然而，尚不清楚对外源蛋白酶活性（作为检测入侵微生物、过敏原和寄生虫的替代物）的感知是否是 IL-1 家族细胞因子的普遍特性。与大多数 IL-1 家族成员一样，IL-36 亚家族（IL-36α、IL-36β 和 IL-36γ）中的细胞因子作为无活性的前体表达，需要在其 N 端的蛋白酶解才能激活。在这里，我们表明与植物、昆虫、真菌和细菌来源的多种常见过敏原相关的蛋白酶（包括豚草、黑麦、屋尘螨、蟑螂和 ）能够加工和激活 IL-36 家族细胞因子，其中 IL-36β 特别容易被多种过敏原激活。此外，几种过敏原的提取物也能加工和增强 IL-1α 的活性。这表明多种 IL-1 家族细胞因子可能作为外源蛋白酶的传感器，将这种活性的检测与这些细胞因子促炎活性的释放联系起来。与先前关于能够激活 IL-1 家族细胞因子的蛋白酶多样性的数据相结合，这表明该细胞因子家族的成员可能作为与感染、组织损伤或程序性坏死相关的异常蛋白酶活性的“活性识别受体”发挥作用。
