| First Author | Greaney AJ | Year | 2020 |
| Journal | J Leukoc Biol | Volume | 108 |
| Issue | 3 | Pages | 773-786 |
| PubMed ID | 32421904 | Mgi Jnum | J:304482 |
| Mgi Id | MGI:6490389 | Doi | 10.1002/JLB.4HI0320-028R |
| Citation | Greaney AJ, et al. (2020) Frontline Science: Anthrax lethal toxin-induced, NLRP1-mediated IL-1beta release is a neutrophil and PAD4-dependent event. J Leukoc Biol 108(3):773-786 |
| abstractText | 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-1beta in mice within hours of toxin challenge. We find IL-1beta 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-1beta originates from hematopoietic cells. LT treatment of neutrophils in vitro did not induce IL-1beta, neutrophil extracellular traps (NETs), or pyroptosis. Although platelets interact closely with neutrophils and are also a potential source of IL-1beta, they were unable to bind or endocytose LT and did not secrete IL-1beta 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-1beta release. DNA sensor AIM2 deficiency, however, did not impact IL-1beta 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. |
