title: Maturation modulates caspase-1-independent responses of dendritic cells to Anthrax lethal toxin.
abstract: Anthrax lethal toxin (LT) contributes to the immune evasion strategy of Bacillus anthracis by impairing the function of cells of the immune system, such as macrophages and dendritic cells (DCs). Macrophages from certain inbred mice strains undergo rapid death upon LT treatment mediated by caspase-1 activation dependent on Nalp1b, an inflammasome component. Rapid LT-induced death is however, not observed in macrophages from human and many mouse strains. Here, we focused on the responses of various murine DCs to LT. Using a variety of knockout mice, we found that depending on the mouse strain, death of bone marrow-derived DCs and macrophages was mediated either by a fast Nalp1b and caspase-1-dependent, or by a slow caspase-1-independent pathway that was triggered by the impairment of MEK1/2 pathways. Caspase-1-independent death was observed in cells of different genetic backgrounds and interestingly occurred only in immature DCs. Maturation, triggered by different types of stimuli, led to full protection of DCs. These studies illustrate that the cellular damage inflicted by LT depends not only on the innate responses but also on the maturation stage of the cell, which modulates the more general caspase-1-independent responses.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Station 15, CH-1015 Lausanne, Switzerland.
authors.forename: Núria
authors.initials: N
authors.lastname: Reig
authors.forename: Aimin
authors.initials: A
authors.lastname: Jiang
authors.forename: Rachael
authors.initials: R
authors.lastname: Couture
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Ogura
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Ira
authors.initials: I
authors.lastname: Mellman
authors.forename: F Gisou
authors.initials: FG
authors.lastname: van der Goot
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism*; D001427:Bacterial Toxins / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D013045:Species Specificity
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C030325:anthrax toxin; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D020170:Caspase 1