Inflammasome-dependent pyroptosis and IL-18 protect against Burkholderia pseudomallei lung infection while IL-1β is deleterious.
Inflammasome-dependent pyroptosis and IL-18 protect against Burkholderia pseudomallei lung infection while IL-1β is deleterious.
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DOI：
10.1371/journal.ppat.1002452
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发表时间：
2011-12
期刊：
影响因子：
6.7
通讯作者：
Re F
中科院分区：
文献类型：
--
作者：
Ceballos-Olvera I;Sahoo M;Miller MA;Del Barrio L;Re F
假性伯克霍尔德菌是一种革兰氏阴性菌，可感染巨噬细胞和其他细胞类型并引起类鼻疽。假假芽孢杆菌与炎性体的相互作用以及焦亡、IL-1β和IL-18在类鼻疽中的作用尚未得到详细研究。在这里，我们发现nod样受体（NLR） NLRP3和NLRC4不同地调节焦亡和IL-1β和IL-18的产生，并且对炎症小体介导的类鼻疽抗性至关重要。巨噬细胞或树突状细胞感染假假芽孢杆菌后产生IL-1β依赖于NLRC4和NLRP3，而焦亡只需要NLRC4。炎性小体成分ASC、caspase-1、NLRC4和NLRP3缺乏的小鼠比WT小鼠更容易感染假芽孢杆菌。Nlrp3-/-小鼠的易感性增加是由于IL-18和IL-1β的产生减少。相比之下，Nlrc4-/-小鼠产生IL-1β和IL-18的量高于WT小鼠，其高易感性是由于减少了焦亡，从而增加了细菌负荷。对IL-18缺陷小鼠的分析显示，IL-18对生存至关重要，主要是因为它能够诱导IFNγ的产生。相比之下，对il - 1ri缺陷小鼠或WT小鼠进行IL-1β或IL-1受体激动剂治疗的研究显示，IL-1β在类鼻炎中具有有害作用。IL-1β的有害作用似乎部分是由于嗜中性粒细胞向肺部过度募集。由于中性粒细胞不表达NLRC4，因此不能进行焦亡，因此它们可能允许假芽孢杆菌在细胞内生长。给药中性粒细胞募集抑制剂IL-1ra或CXCR2中性粒细胞趋化因子受体拮抗剂抗白介素可保护Nlrc4-/-小鼠免受致死剂量的假芽孢杆菌感染，并减少细菌的全身传播。因此，NLRP3和NLRC4炎症小体在类瘤病中具有非冗余的保护作用：NLRC4调节焦亡，而NLRP3调节保护性IL-18和有害IL-1β的产生。类meliosis是由细胞内细菌假马利氏伯克氏菌引起的，这是一种潜在的生物恐怖制剂。在这里，我们研究了假芽孢杆菌与炎性小体的相互作用，炎性小体是一种重要的先天免疫途径，可以调节至少两种宿主对感染的保护反应：1)促炎细胞因子IL-1β和IL-18的分泌，以及2)诱导焦亡（一种限制细胞内细菌生长的细胞死亡形式）。使用类鼻疽小鼠模型，我们表明两个不同的炎性小体被假芽孢杆菌感染激活。一种是含有nod样受体（NLR） NLRP3，介导IL-1β和IL-18诱导。另一种含有不同的NLR，称为NLRC4，并介导焦亡。焦亡和IL-18的产生对假芽孢杆菌的抗性同样重要。令人惊讶的是，IL-1β在类鼻疽中被发现是有害的。IL-1β在类melidosis中的有害作用部分是由于嗜中性粒细胞过度募集到肺部。我们发现中性粒细胞不表达NLRC4，不能进行焦亡，因此可能允许假芽孢杆菌在细胞内复制，导致细菌负担和发病率/死亡率增加。因此，NLRP3和NLRC4炎症小体在类瘤病中具有非冗余的保护作用：NLRC4调节焦亡，而NLRP3调节保护性IL-18和有害IL-1β的产生。
Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and other cell types and causes melioidosis. The interaction of B. pseudomallei with the inflammasome and the role of pyroptosis, IL-1β, and IL-18 during melioidosis have not been investigated in detail. Here we show that the Nod-like receptors (NLR) NLRP3 and NLRC4 differentially regulate pyroptosis and production of IL-1β and IL-18 and are critical for inflammasome-mediated resistance to melioidosis. In vitro production of IL-1β by macrophages or dendritic cells infected with B. pseudomallei was dependent on NLRC4 and NLRP3 while pyroptosis required only NLRC4. Mice deficient in the inflammasome components ASC, caspase-1, NLRC4, and NLRP3, were dramatically more susceptible to lung infection with B. pseudomallei than WT mice. The heightened susceptibility of Nlrp3-/- mice was due to decreased production of IL-18 and IL-1β. In contrast, Nlrc4-/- mice produced IL-1β and IL-18 in higher amount than WT mice and their high susceptibility was due to decreased pyroptosis and consequently higher bacterial burdens. Analyses of IL-18-deficient mice revealed that IL-18 is essential for survival primarily because of its ability to induce IFNγ production. In contrast, studies using IL-1RI-deficient mice or WT mice treated with either IL-1β or IL-1 receptor agonist revealed that IL-1β has deleterious effects during melioidosis. The detrimental role of IL-1β appeared to be due, in part, to excessive recruitment of neutrophils to the lung. Because neutrophils do not express NLRC4 and therefore fail to undergo pyroptosis, they may be permissive to B. pseudomallei intracellular growth. Administration of neutrophil-recruitment inhibitors IL-1ra or the CXCR2 neutrophil chemokine receptor antagonist antileukinate protected Nlrc4-/- mice from lethal doses of B. pseudomallei and decreased systemic dissemination of bacteria. Thus, the NLRP3 and NLRC4 inflammasomes have non-redundant protective roles in melioidosis: NLRC4 regulates pyroptosis while NLRP3 regulates production of protective IL-18 and deleterious IL-1β. The disease melioidosis is caused by the intracellular bacterium Burkholderia pseudomallei, a potential bioterrorism agent. Here we examined the interaction of B. pseudomallei with the inflammasome, an important innate immune pathway that regulates at least two host responses protective against infections: 1) secretion of the proinflammatory cytokines IL-1β and IL-18 and 2) induction of pyroptosis, a form of cell death that restricts intracellular bacteria growth. Using a mouse model of melioidosis we show that two distinct inflammasomes are activated by B. pseudomallei infection. One, containing the Nod-like receptor (NLR) NLRP3, mediates IL-1β and IL-18 induction. The other contains a different NLR called NLRC4 and mediates pyroptosis. Pyroptosis and IL-18 production were equally important for resistance to B. pseudomallei. Surprisingly, IL-1β was found to be deleterious in melioidosis. The detrimental role of IL-1β during melioidosis was due, in part, to excessive recruitment of neutrophils to the lung. We show that neutrophils do not express NLRC4, fail to undergo pyroptosis, and, therefore, may be permissive to B. pseudomallei intracellular replication leading to increased bacterial burden and morbidity/mortality. Thus, the NLRP3 and NLRC4 inflammasomes have non-redundant protective roles in melioidosis: NLRC4 regulates pyroptosis while NLRP3 regulates production of protective IL-18 and deleterious IL-1β.
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