Citrullination alters immunomodulatory function of LL-37 essential for prevention of endotoxin-induced sepsis.
Citrullination alters immunomodulatory function of LL-37 essential for prevention of endotoxin-induced sepsis.
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DOI：
10.4049/jimmunol.1303062
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发表时间：
2014-06-01
期刊：
影响因子：
--
通讯作者：
Potempa J
中科院分区：
文献类型：
--
作者：
Koziel J;Bryzek D;Sroka A;Maresz K;Glowczyk I;Bielecka E;Kantyka T;Pyrć K;Svoboda P;Pohl J;Potempa J
长春花素LL-37通过杀灭入侵微生物和调节炎症反应，在先天免疫中发挥重要作用。这些活性取决于由精氨酸和赖氨酸残基赋予的多肽的阳离子特性。在体内的炎症部位，LL-37暴露于由炎症细胞释放的一种酶--肽基精氨酸脱亚胺酶(PAD)。因此，我们假设，PAD介导的精氨酸残基的瓜氨酸化将取消其免疫调节功能。我们发现，当瓜氨酸，LL-37在中和内毒素的促炎活性方面至少降低了40倍，这是因为它对内毒素的亲和力显著降低。此外，瓜氨酸化的LL-37分别通过TLR2和TLR3抑制巨噬细胞对LTA和Poly(I：C)信号的反应的能力显著降低。此外，与天然的LL-37形成鲜明对比的是，在D-氨基半乳糖敏感的内毒素休克小鼠模型中，修饰的多肽完全失去了预防发病率和死亡率的能力。事实上，给予瓜氨酸化的LL-37和内毒素实际上加剧了败血症，因为LL-37无法中和内毒素，随后由于血清IL-6水平的增加而增强了全身炎症。重要的是，脓毒症小鼠的血清显示PAD活性增加，这与瓜氨酸化水平密切相关，表明PAD驱动的蛋白质修饰在体内发生。由于LL-37是一种潜在的治疗脓毒症的方法，在给药之前应该进行仔细的分析，以确保在接受治疗的患者中不会产生瓜氨酸肽。
Cathelicidin LL-37 plays an essential role in innate immunity by killing invading microorganisms and regulating the inflammatory response. These activities depend on the cationic character of the peptide, which is conferred by arginine and lysine residues. At inflammatory foci in vivo, LL-37 is exposed to peptidyl arginine deiminase (PAD), an enzyme released by inflammatory cells. Therefore, we hypothesised that PAD-mediated citrullination of the arginine residues within LL-37 will abrogate its immunomodulatory functions. We found that when citrullinated, LL-37 was at least 40 times less efficient at neutralising the proinflammatory activity of LPS due to a marked decrease in its affinity for endotoxin. Also, the ability of citrullinated LL-37 to quench macrophage responses to LTA and Poly (I:C) signalling via TLR2 and TLR3, respectively, was significantly reduced. Furthermore, in stark contrast to native LL-37, the modified peptide completely lost the ability to prevent morbidity and mortality in a mouse model of D-galactosamine-sensitised endotoxin shock. In fact, administration of citrullinated LL-37 plus endotoxin actually exacerbated sepsis due to the inability of LL-37 to neutralise LPS and the subsequent enhancement of systemic inflammation due to increased serum levels of IL-6. Importantly, serum from septic mice showed increased PAD activity, which strongly correlated with the level of citrullination, indicating that PAD-driven protein modification occurs in vivo. Since LL-37 is a potential treatment for sepsis, its administration should be preceded by a careful analysis to ensure that the citrullinated peptide, is not generated in treated patients.
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