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Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its phosphokinase PknF.

ABSTRACT: Mycobacterium tuberculosis (Mtb) has evolved to evade host innate immunity by interfering with macrophage functions. Interleukin-1β (IL-1β) is secreted by macrophages after the activation of the inflammasome complex and is crucial for host defense against Mtb infections. We have previously shown that Mtb is able to inhibit activation of the AIM2 inflammasome and subsequent pyroptosis. Here we show that Mtb is also able to inhibit host cell NLRP3 inflammasome activation and pyroptosis. We identified the serine/threonine kinase PknF as one protein of Mtb involved in the NLRP3 inflammasome inhibition, since the pknF deletion mutant of Mtb induces increased production of IL-1β in bone marrow-derived macrophages (BMDMs). The increased production of IL-1β was dependent on NLRP3, the adaptor protein ASC and the protease caspase-1, as revealed by studies performed in gene-deficient BMDMs. Additionally, infection of BMDMs with the pknF deletion mutant resulted in increased pyroptosis, while the IL-6 production remained unchanged compared to Mtb-infected cells, suggesting that the mutant did not affect the priming step of inflammasome activation. In contrast, the activation step was affected since potassium efflux, chloride efflux and the generation of reactive oxygen species played a significant role in inflammasome activation and subsequent pyroptosis mediated by the Mtb pknF mutant strain. In conclusion, we reveal here that the serine/threonine kinase PknF of Mtb plays an important role in innate immune evasion through inhibition of the NLRP3 inflammasome.

SUBMITTER: Rastogi S

PROVIDER: S-EPMC8321130 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Genipin inhibits NLRP3 and NLRC4 inflammasome activation via autophagy suppression.

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| S-EPMC3657562 | biostudies-literature

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| S-EPMC10808187 | biostudies-literature

Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by <i>Mycobacterium tuberculosis</i> in Infected Macrophages.

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| S-EPMC7422798 | biostudies-literature

Exercise Inhibits NLRP3 Inflammasome Activation in Obese Mice via the Anti-Inflammatory Effect of Meteorin-like.

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| S-EPMC8700724 | biostudies-literature

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