Macrophage activation redirects yersinia-infected host cell death from apoptosis to caspase-1-dependent pyroptosis.
Macrophage activation redirects yersinia-infected host cell death from apoptosis to caspase-1-dependent pyroptosis.
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DOI：
10.1371/journal.ppat.0030161
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发表时间：
2007-11
期刊：
影响因子：
6.7
通讯作者：
Cookson BT
中科院分区：
文献类型：
--
作者：
Bergsbaken T;Cookson BT
耶尔森氏菌感染巨噬细胞会导致 YopJ 依赖性细胞凋亡，而幼稚巨噬细胞对这种形式的细胞死亡高度敏感。先前的研究表明，感染前用脂多糖（LPS）激活的巨噬细胞能够抵抗 YopJ 依赖性细胞死亡；我们发现这同时使得巨噬细胞容易被 YopJ− 假结核耶尔森氏菌 (Yptb) 杀死。 YopJ−Yptb 诱导的巨噬细胞死亡依赖于 caspase-1 激活，导致小分子快速渗透，随后发生膜破裂和 DNA 损伤，并伴随促炎性白细胞介素 18 的裂解和释放。诱导 caspase-1 依赖性死亡或细胞焦亡需要细菌 III 型易位子，但不需要已知的易位蛋白。野生型 Yptb 感染也会引发细胞焦亡：在活化的巨噬细胞中，YopJ 依赖性促凋亡 caspase-3 的激活显着延迟，并导致 caspase-1 依赖性细胞焦亡。向易感性的转变并不限于 LPS 激活；在用其他 Toll 样受体 (TLR) 配体激活的巨噬细胞和完整的非活细菌中也发现了这种现象。 Yptb感染引发体内巨噬细胞激活和caspase-1激活。鼠疫耶尔森氏菌感染激活的巨噬细胞也刺激 caspase-1 激活。这些结果表明，在耶尔森氏菌感染过程中，TLR 和其他激活配体触发的宿主信号传导通过从非炎性细胞凋亡转变为炎性细胞焦亡，重新定向了宿主细胞死亡机制和死亡的下游后果。致病性耶尔森氏菌是能够与宿主免疫细胞相互作用并抑制其功能的细菌。巨噬细胞是有效的抗菌免疫细胞，可以消除入侵的微生物，是耶尔森氏菌感染期间的主要目标。耶尔森氏菌通过细胞凋亡触发静息巨噬细胞死亡，这一过程被认为有利于耶尔森氏菌在感染早期的生长，因为重要的宿主细胞在不干扰周围组织的情况下被消除。然而，具有增强抗菌活性的活化巨噬细胞在控制耶尔森菌感染中发挥着至关重要的作用。为了阐明成功防御感染的机制，作者研究了活化的巨噬细胞对耶尔森氏菌的反应，结果揭示了一种称为焦亡的促炎细胞死亡途径的诱导。与细胞凋亡不同，焦亡释放出能够增强免疫反应和清除细菌的炎症介质。在受感染的宿主组织中观察到巨噬细胞活化和细胞焦亡。因此，调节细胞死亡机制对于有效应对耶尔森氏菌感染非常重要：抵抗细胞凋亡的活化巨噬细胞被重定向以利用细胞焦亡，这是一种促进宿主抵抗的炎症过程。
Infection of macrophages by Yersinia species results in YopJ-dependent apoptosis, and naïve macrophages are highly susceptible to this form of cell death. Previous studies have demonstrated that macrophages activated with lipopolysaccharide (LPS) prior to infection are resistant to YopJ-dependent cell death; we found this simultaneously renders macrophages susceptible to killing by YopJ− Yersinia pseudotuberculosis (Yptb). YopJ− Yptb-induced macrophage death was dependent on caspase-1 activation, resulting in rapid permeability to small molecules, followed by membrane breakdown and DNA damage, and accompanied by cleavage and release of proinflammatory interleukin-18. Induction of caspase-1-dependent death, or pyroptosis, required the bacterial type III translocon but none of its known translocated proteins. Wild-type Yptb infection also triggered pyroptosis: YopJ-dependent activation of proapoptotic caspase-3 was significantly delayed in activated macrophages and resulted in caspase-1-dependent pyroptosis. The transition to susceptibility was not limited to LPS activation; it was also seen in macrophages activated with other Toll-like receptor (TLR) ligands and intact nonviable bacteria. Yptb infection triggered macrophage activation and activation of caspase-1 in vivo. Y. pestis infection of activated macrophages also stimulated caspase-1 activation. These results indicate that host signaling triggered by TLR and other activating ligands during the course of Yersinia infection redirects both the mechanism of host cell death and the downstream consequences of death by shifting from noninflammatory apoptosis to inflammatory pyroptosis. Pathogenic Yersinia are bacteria capable of interacting with host immune cells and inhibiting their function. Macrophages are potent antimicrobial immune cells that eliminate invading microbes, and represent a major target for Yersinia during infection. Yersinia triggers death of resting macrophages by apoptosis, a process thought to be advantageous for Yersinia growth during early stages of infection because important host cells are eliminated without perturbing the surrounding tissue. However, activated macrophages with enhanced antimicrobial activity play a crucial role in controlling Yersinia infection. To elucidate the mechanisms involved in successful defense against infection, the authors investigated the response of activated macrophages to Yersinia, which revealed induction of a proinflammatory cell death pathway termed pyroptosis. Unlike apoptosis, pyroptosis unleashes inflammatory mediators capable of enhancing immune responses and clearing bacteria. Macrophage activation and pyroptosis was observed in infected host tissue. Thus, regulating the mechanism of cell death is important for effective responses to Yersinia infection: activated macrophages resisting apoptosis are redirected to utilize pyroptosis, an inflammatory process facilitating host resistance.
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