Premium
Frontline Science: Anthrax lethal toxin‐induced, NLRP1‐mediated IL‐1β release is a neutrophil and PAD4‐dependent event
Author(s) -
Greaney Allison J.,
Portley Makayla K.,
O'Mard Danielle,
Crown Devorah,
Maier Nolan K.,
Mendenhall Megan A.,
MayerBarber Katrin D.,
Leppla Stephen H.,
Moayeri Mahtab
Publication year - 2020
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.4hi0320-028r
Subject(s) - neutrophil extracellular traps , biology , inflammasome , priming (agriculture) , pyroptosis , immunology , caspase 1 , microbiology and biotechnology , inflammation , botany , germination
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‐1β in mice within hours of toxin challenge. We find IL‐1β 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‐1β originates from hematopoietic cells. LT treatment of neutrophils in vitro did not induce IL‐1β, neutrophil extracellular traps (NETs), or pyroptosis. Although platelets interact closely with neutrophils and are also a potential source of IL‐1β, they were unable to bind or endocytose LT and did not secrete IL‐1β 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‐1β release. DNA sensor AIM2 deficiency, however, did not impact IL‐1β 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.