Bacillus anthracis induces NLRP3 inflammasome activation and caspase-8-mediated apoptosis of macrophages to promote lethal anthrax
In: Proceedings of the National Academy of Sciences of the United States, Jg. 119 (2022-01-11), Heft 2, S. 1aa- (9S.)
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Zugriff:
Lethal toxin (LeTx)-mediated killing of myeloid cells is essential for Bacillus anthracis, the causative agent of anthrax, to establish systemic infection and induce lethal anthrax. The 'LeTx-sensitive' NLRP1b inflammasome of BALB/c and 129S macrophages swiftly responds to LeTx intoxication with pyroptosis and secretion of interleukin (IL)-1p. However, human NLRP1 is nonresponsive to LeTx, prompting us to investigate B. anthracis host-pathogen interactions in C57BL/6J (B6) macrophages and mice that also lack a LeTx-sensitive Nlrp1b allele. Unexpectedly, we found that LeTx intoxication and live B. anthracis infection of B6 macrophages elicited robust secretion of IL-1p, which critically relied on the NLRP3 inflammasome. TNF signaling through both TNF receptor 1 (TNF-R1) and TNF-R2 were required for B. anthracis-induced NLRP3 inflammasome activation, which was further controlled by RIPK1 kinase activity and LeTx-mediated proteolytic inactivation of MAP kinase signaling. In addition to activating the NLRP3 inflammasome, LeTx-induced MAPKK inactivation and TNF production sensitized B. anthracis-infected macrophages to robust RIPK1- and caspase-8-dependent apoptosis. In agreement, purified LeTx triggered RIPK1 kinase activity- and caspase-8-dependent apoptosis only in macrophages primed with TNF or following engagement of TRIF-dependent Toll-like receptors. Consistently, genetic and pharmacological inhibition of RIPK1 inhibited NLRP3 inflammasome activation and apoptosis of LeTx-intoxicated and B. anthracis-infected macrophages. Caspase-8/RIPK3-deficient mice were significantly protected from B. anthracis-induced lethality, demonstrating the in vivo pathophysiological relevance of this cytotoxic mechanism. Collectively, these results establish TNF- and RIPK1 kinase activity-dependent NLRP3 inflammasome activation and macrophage apoptosis as key host-pathogen mechanisms in lethal anthrax. anthrax | TNF | infection | apoptosis | NLRP3 inflammasome
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Bacillus anthracis induces NLRP3 inflammasome activation and caspase-8-mediated apoptosis of macrophages to promote lethal anthrax
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Autor/in / Beteiligte Person: | Hauwermeiren, Filip Van ; Opdenbosch, Nina Van ; Gorp, Hanne Van ; Vasconcelos, Nathalia de ; Loo, Geert van ; Vandenabeele, Peter ; Kanneganti, Thirumala-Devi ; Lamkanfi, Mohamed |
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Zeitschrift: | Proceedings of the National Academy of Sciences of the United States, Jg. 119 (2022-01-11), Heft 2, S. 1aa- (9S.) |
Veröffentlichung: | 2022 |
Medientyp: | academicJournal |
ISSN: | 0027-8424 (print) |
DOI: | 10.1073/pnas.2116415119 |
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