Neutrophil Elastase-mediated proteolysis activates the anti-inflammatory cytokine IL-36 Receptor antagonist.
Neutrophil Elastase-mediated proteolysis activates the anti-inflammatory cytokine IL-36 Receptor antagonist.
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DOI：
10.1038/srep24880
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发表时间：
2016-04-22
影响因子：
4.6
通讯作者：
Wittmann M
中科院分区：
文献类型：
--
作者：
Macleod T;Doble R;McGonagle D;Wasson CW;Alase A;Stacey M;Wittmann M
调节IL-36α、-β和-γ的白介素-36受体拮抗剂（IL-36Ra）与银屑病炎症有关，特别是脓疱型银屑病亚型的功能丧失突变。与其他IL-1超家族蛋白一样，IL-36成员需要n端切割才能获得充分的生物活性，但IL-36Ra激活的机制尚不清楚。使用不同的血液白细胞和皮肤常驻细胞制剂，以及重组蛋白，我们已经确定中性粒细胞弹性酶，而不是其他中性粒细胞衍生的蛋白酶，将IL-36Ra切割成其高活性的拮抗形式。这种加工形式的IL-36Ra的活性在人原代真皮成纤维细胞和角质形成细胞以及皮肤等量细胞中得到证实。与全长IL-36Ra相比，加入裂解的IL-36Ra后，IL-36γ诱导的IL-8和趋化因子配体20 （CCL20）水平有显著的剂量依赖性降低。通过激活IL-36Ra，中性粒细胞衍生的蛋白酶可以抑制IL-36诱导的趋化因子的产生，包括IL-8和CCL20，并减少炎症细胞的进一步浸润。这些发现强烈提示中性粒细胞弹性酶是IL-36Ra生物学功能的关键酶，中性粒细胞可以在银屑病炎症中发挥调节作用，平衡IL-36的促炎活性。
The interleukin-36 receptor antagonist (IL-36Ra) which regulates IL-36α, -β and -γ is linked to psoriatic inflammation, especially loss-of-function mutations in pustular psoriasis subtypes. As observed with other IL-1 superfamily proteins, the IL-36 members require N-terminal cleavage for full biological activity but the mechanisms of IL-36Ra activation remain poorly defined. Using different blood leukocyte and skin resident cell preparations, and recombinant proteins, we have identified that neutrophil elastase, but not other neutrophil derived proteases, cleaves IL-36Ra into its highly active antagonistic form. The activity of this processed form of IL-36Ra was confirmed in human primary dermal fibroblasts and keratinocytes and in skin equivalents. A significant dose dependent reduction of IL-36γ induced IL-8 and chemokine ligand 20 (CCL20) levels were detected following addition of the cleaved IL-36Ra compared to full length IL-36Ra. By activating IL-36Ra, the neutrophil derived protease can inhibit IL-36 induced chemokine production, including IL-8 and CCL20, and reduce further inflammatory cell infiltration. These findings strongly indicate neutrophil elastase to be a key enzyme in the biological function of IL-36Ra and that neutrophils can play a regulatory role in psoriatic inflammation with regard to balancing the pro-inflammatory activity of IL-36.