期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 108, 期 3, 页码 773-786出版社
OXFORD UNIV PRESS
DOI: 10.1002/JLB.4HI0320-028R
关键词
inflammasome; IL-18; pyroptosis; NETs; IL-1 beta
资金
- Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI001032, ZIAAI001207] Funding Source: NIH RePORTER
Anthrax lethal toxin (LT) is a protease that activates the NLRP1b inflammasome sensor in certain rodent strains. Unlike better-studied sensors, relatively little is known about the priming requirements for NLRP1b. In this study, we investigate the rapid and striking priming-independent LT-induced release of IL-1 beta in mice within hours of toxin challenge. We find IL-1 beta release to be a NLRP1b- and caspase-1-dependent, NLRP3 and caspase-11-independent event that requires both neutrophils and peptidyl arginine deiminiase-4 (PAD4) activity. The simultaneous LT-induced IL-18 response is neutrophil-independent. Bone marrow reconstitution experiments in mice show toxin-induced IL-1 beta originates from hematopoietic cells. LT treatment of neutrophils in vitro did not induce IL-1 beta, neutrophil extracellular traps (NETs), or pyroptosis. Although platelets interact closely with neutrophils and are also a potential source of IL-1 beta, they were unable to bind or endocytose LT and did not secrete IL-1 beta in response to the toxin. LT-treated mice had higher levels of cell-free DNA and HMGB1 in circulation than PBS-treated controls, and treatment of mice with recombinant DNase reduced the neutrophil- and NLRP1-dependent IL-1 beta release. DNA sensor AIM2 deficiency, however, did not impact IL-1 beta release. These data, in combination with the findings on PAD4, suggest a possible role for in vivo NETs or cell-free DNA in cytokine induction in response to LT challenge. Our findings suggest a complex interaction of events and/or mediators in LT-treated mice with the neutrophil as a central player in induction of a profound and rapid inflammatory response to toxin.
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