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Pseudomonas aeruginosa (PA) is an opportunistic pathogen that causes the relapse of illness in immunocompromised patients, leading to prolonged hospitalization, increased medical expense, and death. In this report, we show that PA invades natural killer (NK) cells and induces phagocytosis-induced cell death (PICD) of lymphocytes. In vivo tumor metastasis was augmented by PA infection, with a significant reduction in NK cell number. Adoptive transfer of NK cells mitigated PA-induced metastasis. Internalization of PA into NK cells was observed by transmission electron microscopy. In addition, PA invaded NK cells via phosphoinositide 3-kinase (PI3K) activation, and the phagocytic event led to caspase 9-dependent apoptosis of NK cells. PA-mediated NK cell apoptosis was dependent on activation of mitogen-activated protein (MAP) kinase and the generation of reactive oxygen species (ROS). These data suggest that the phagocytosis of PA by NK cells is a critical event that affects the relapse of diseases in immunocompromised patients, such as those with cancer, and provides important insights into the interactions between PA and NK cells., Author Summary Phagocytic leukocytes, including neutrophils and macrophages, are critical for innate immunity against invading bacteria. Binding and internalization of bacteria by these immune cells stimulates a variety of anti-microbial activities. Although the immune cells are specialized for elimination of bacteria, cellular apoptosis by bacterial phagocytosis has emerged as an important mechanism of pathogenesis. NK cells are non-phagocytic lymphocytes that are responsible for innate immunity via elimination of virus or bacteria-infected cells, as well as transformed cells. We found that PA invades NK cells and that this phagocytic event results in the generation of ROS within the NK cells, leading to apoptosis. The elimination of NK cells, at least in part, may be responsible for the relapse in PA-infected cancer patients. Based on these findings, studies on the interactions between bacterial determinants and host receptors should provide further insight into the mechanisms of bacterial pathogenesis.

Thioredoxin-interacting protein (TXNIP) has multiple functions, including tumor suppression and involvement in cell proliferation and apoptosis. However, its role in the inflammatory process remains unclear. In this report, we demonstrate that Txnip−/− mice are significantly more susceptible to lipopolysaccharide (LPS)-induced endotoxic shock. In response to LPS, Txnip−/− macrophages produced significantly higher levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS), and an iNOS inhibitor rescued Txnip−/− mice from endotoxic shock-induced death, demonstrating that NO is a major factor in TXNIP-mediated endotoxic shock. This susceptibility phenotype of Txnip−/− mice occurred despite reduced IL-1β secretion due to increased S-nitrosylation of NLRP3 compared to wild-type controls. Taken together, these data demonstrate that TXNIP is a novel molecule that links NO synthesis and NLRP3 inflammasome activation during endotoxic shock., Author Summary TXNIP has many biological functions, including the inhibition of tumor growth, suppression of hepatocarcinogenesis, and regulation of glucose metabolism and reactive oxygen species (ROS) generation in different cell types. However, little is known about its role in the inflammatory process. In this study, our results demonstrate that TXNIP plays a critical role in the control of lethal endotoxin-induced shock by controlling NO production in innate immune cells via the regulation of iNOS expression. This regulation is mediated through changes in the activation and translocation of NF-κB that affect the NF-κB/iNOS pathway. In addition, excessive NO reduces the production of IL-1β via S-nitrosylation of the NLRP3 inflammasome. Subsequently, the survival of Txnip−/− mice is significantly decreased due to hypothermia and hypoglycemia. Overall, these results suggest that TXNIP is a novel therapeutic target for the treatment of inflammatory diseases.