4592 total record number 282 records this year

NLRP3 and Potassium Efflux Drive Rapid IL-1 Release from Primary Human Monocytes during Toxoplasma gondii Infection

Gov, L;Schneider, CA;Lima, TS;Pandori, W;Lodoen, MB;

IL-1 is produced by myeloid cells and acts as a critical mediator of host defense during infection and injury. We found that the intracellular protozoan parasite Toxoplasma gondii induced an early IL-1 response (within 4 h) in primary human peripheral blood monocytes isolated from healthy donors. This process involved upregulation of IL-1, IL-1RN (IL-1R antagonist), and NLRP3 transcripts, de novo protein synthesis, and the release of pro- and mature IL-1 from infected primary monocytes. The released pro-IL-1 was cleavable to mature bioactive IL-1 in the extracellular space by the protease caspase-1. Treatment of primary monocytes with the NLRP3 inhibitor MCC950 or with extracellular potassium significantly reduced IL-1 cleavage and release in response to T. gondii infection, without affecting the release of TNF-, and indicated a role for the inflammasome sensor NLRP3 and for potassium efflux in T. gondii-induced IL-1 production. Interestingly, T. gondii infection did not induce an IL-1 response in primary human macrophages derived from the same blood donors as the monocytes. Consistent with this finding, NLRP3 was downregulated during the differentiation of monocytes to macrophages and was not induced in macrophages during T. gondii infection. To our knowledge, these findings are the first to identify NLRP3 as an inflammasome sensor for T. gondii in primary human peripheral blood cells and to define an upstream regulator of its activation through the release of intracellular potassium.

  • PubMed ID: 28904126