During acute Pseudomonas aeruginosa infection, the inflammatory response is essential for bacterial clearance. Neutrophil recruitment can be initiated following the assembly of an inflammasome within sentinel macrophages, leading to activation of caspase‐1, which in turn triggers macrophage pyroptosis and IL‐1β/IL‐18 maturation. Inflammasome formation can be induced by a number of bacterial determinants, including Type III secretion systems (T3SSs) or pore‐forming toxins, or, alternatively, by lipopolysaccharide (LPS) via caspase‐11 activation. Surprisingly, previous studies indicated that a T3SS‐induced inflammasome increased pathogenicity in mouse models of P. aeruginosa infection. Here, we investigated the immune reaction of mice infected with a T3SS‐negative P. aeruginosa strain (IHMA879472). Virulence of this strain relies on ExlA, a secreted pore‐forming toxin. IHMA879472 promoted massive neutrophil infiltration in infected lungs, owing to efficient priming of toll‐like receptors, and thus enhanced the expression of inflammatory proteins including pro‐IL‐1β and TNF‐α. However, mature‐IL‐1β and IL‐18 were undetectable in wild‐type mice, suggesting that ExlA failed to effectively activate caspase‐1. Nevertheless, caspase‐1/11 deficiency improved survival following infection with IHMA879472, as previously described for T3SS+ bacteria. We conclude that the detrimental effect associated with the ExlA‐induced inflammasome is probably not due to hyperinflammation, rather it stems from another inflammasome‐dependent process.

中文翻译：

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绿脓杆菌的 ExlA 成孔毒素激活炎症小体对宿主有害。

在急性铜绿假单胞菌感染期间，炎症反应对于细菌清除至关重要。在前哨巨噬细胞内组装炎性体后，可以启动中性粒细胞募集，导致 caspase-1 激活，进而触发巨噬细胞焦亡和 IL-1β/IL-18 成熟。炎症小体的形成可以由许多细菌决定因素诱导，包括 III 型分泌系统 (T3SS) 或成孔毒素，或者，脂多糖 (LPS) 通过 caspase-11 激活。令人惊讶的是，先前的研究表明，T3SS 诱导的炎症小体增加了铜绿假单胞菌感染小鼠模型的致病性。在这里，我们研究了感染 T3SS 阴性的小鼠的免疫反应铜绿假单胞菌菌株 (IHMA879472)。该菌株的毒力依赖于 ExlA，一种分泌的成孔毒素。IHMA879472 促进受感染肺中的大量中性粒细胞浸润，这是由于 Toll 样受体的有效启动，从而增强了炎症蛋白包括 pro-IL-1β 和 TNF-α 的表达。然而，成熟的 IL-1β 和 IL-18 在野生型小鼠中检测不到，表明 ExlA 未能有效激活 caspase-1。然而，如先前针对 T3SS+ 细菌所述，caspase-1/11 缺陷改善了 IHMA879472 感染后的存活率。我们得出结论，与 ExlA 诱导的炎症小体相关的有害影响可能不是由于过度炎症，而是源于另一个依赖炎症小体的过程。