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Thioredoxin-Interacting Protein Promotes Phagosomal Acidification Upon Exposure to Escherichia coli Through Inflammasome-Mediated Caspase-1 Activation in Macrophages.


ABSTRACT: In host defense, it is crucial to maintain the acidity of the macrophage phagosome for effective bacterial clearance. However, the mechanisms governing phagosomal acidification upon exposure to gram-negative bacteria have not been fully elucidated. In this study, we demonstrate that in macrophages exposed to Escherichia coli, the thioredoxin-interacting protein (TXNIP)-associated inflammasome plays a role in pH modulation through the activated caspase-1-mediated inhibition of NADPH oxidase. While there was no difference in early-phase bacterial engulfment between Txnip knockout (KO) macrophages and wild-type (WT) macrophages, Txnip KO macrophages were less efficient at destroying intracellular bacteria in the late phase, and their phagosomes failed to undergo appropriate acidification. These phenomena were associated with reactive oxygen species production and were reversed by treatment with an NADPH oxidase inhibitor or a caspase inhibitor. In line with these results, Txnip KO mice were more susceptible to both intraperitoneally administered E. coli and sepsis induced by cecum ligation and puncture than WT mice. Taken together, this study suggests that the TXNIP-associated inflammasome-caspase-1 axis regulates NADPH oxidase to modulate the pH of the phagosome, controlling bacterial clearance by macrophages.

SUBMITTER: Yoon SJ 

PROVIDER: S-EPMC6861186 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Thioredoxin-Interacting Protein Promotes Phagosomal Acidification Upon Exposure to <i>Escherichia coli</i> Through Inflammasome-Mediated Caspase-1 Activation in Macrophages.

Yoon Sung-Jin SJ   Jo Dong Hyun DH   Park Seung-Ho SH   Park Jun-Young JY   Lee Yoo-Kyung YK   Lee Moo-Seung MS   Min Jeong-Ki JK   Jung Haiyoung H   Kim Tae-Don TD   Yoon Suk Ran SR   Chung Su Wol SW   Kim Jeong Hun JH   Choi Inpyo I   Park Young-Jun YJ  

Frontiers in immunology 20191112


In host defense, it is crucial to maintain the acidity of the macrophage phagosome for effective bacterial clearance. However, the mechanisms governing phagosomal acidification upon exposure to gram-negative bacteria have not been fully elucidated. In this study, we demonstrate that in macrophages exposed to <i>Escherichia coli</i>, the thioredoxin-interacting protein (TXNIP)-associated inflammasome plays a role in pH modulation through the activated caspase-1-mediated inhibition of NADPH oxidas  ...[more]

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2022-11-04 | GSE215036 | GEO