Caspase-11-dependent pyroptosis of lung epithelial cells protects from melioidosis while caspase-1 mediates macrophage pyroptosis and production of IL-18

Abstract

Infection with Burkholderia pseudomallei or B. thailandensis triggers activation of the NLRP3 and NLRC4 inflammasomes leading to release of IL-1β and IL-18 and death of infected macrophages by pyroptosis, respectively. The non-canonical inflammasome composed of caspase-11 is also activated by these bacteria and provides protection through induction of pyroptosis. The recent generation of bona fide caspase-1-deficient mice allowed us to reexamine in a mouse model of pneumonic melioidosis the role of caspase-1 independently of caspase-11 (that was also absent in previously generated Casp1-/- mice). Mice lacking either caspase-1 or caspase-11 were significantly more susceptible than wild type mice to intranasal infection with B. thailandensis. Absence of caspase-1 completely abolished production of IL-1β and IL-18 as well as pyroptosis of infected macrophages. In contrast, in mice lacking caspase-11 IL-1β and IL-18 were produced at normal level and macrophages pyroptosis was only marginally affected. Adoptive transfer of bone marrow indicated that caspase-11 exerted its protective action both in myeloid cells and in radio-resistant cell types. B. thailandensis was shown to readily infect mouse lung epithelial cells triggering pyroptosis in a caspase-11-dependent way in vitro and in vivo. Importantly, we show that lung epithelial cells do not express inflammasomes components or caspase-1 suggesting that this cell type relies exclusively on caspase-11 for undergoing cell death in response to bacterial infection. Finally, we show that IL-18’s protective action in melioidosis was completely dependent on its ability to induce IFNγ production. In turn, protection conferred by IFNγ against melioidosis was dependent on generation of ROS through the NADPH oxidase but independent of induction of caspase-11. Altogether, our results identify two non-redundant protective roles for caspase-1 and caspase-11 in melioidosis: Caspase-1 primarily controls pyroptosis of infected macrophages and production of IL-18. In contrast, caspase-11 mediates pyroptosis of infected lung epithelial cells.

The inflammasomes, immune guardians at defence barriers

“…[80][81][82][83] It has been suggested that as some of these cells do not express the inflammasome component, caspase-11 is responsible for the inflammasome response to infections, probably by direct biding of LPS. 84 These differential results highlight the importance of analysing the expression of inflammasome components in the lung epithelial cell lines before conducting inflammasome experiments and the need to work in mouse and human primary cells.…”

“…For instance, the involvement of caspase‐1 is not clear because some studies show that epithelial cell lines (Beas2Bs, 16HBE, Calu‐3) and also primary cells (human bronchial epithelial cells) express little to no caspase‐1 in an infection model, whereas others show a role for caspase‐1 in epithelial cells (for instance in Beas2Bs, mouse tracheobronchial epithelial cells and A549) . It has been suggested that as some of these cells do not express the inflammasome component, caspase‐11 is responsible for the inflammasome response to infections, probably by direct biding of LPS . These differential results highlight the importance of analysing the expression of inflammasome components in the lung epithelial cell lines before conducting inflammasome experiments and the need to work in mouse and human primary cells.…”

Interferon inducible GBPs restrict Burkholderia thailandensis motility induced cell-cell fusion

“…These findings suggest that B. thailandensis is generally well controlled by cell-autonomous immunity in mammals. While GBPs appear to play a minor role in direct promotion of inflammasome activation, previous studies have established an important role for many inflammasome signaling components and the downstream inflammatory cytokines in both protection and immunopathology during B. thailandensis and B. pseudomallei infections [8][9][10]31,42]. Many pathogens encode bacterial factors that nucleate actin polymerization that is dependent upon the Arp2/3 complex [43].…”

“…Burkholderia thailandensis is an opportunistic intracellular pathogen that induces multinucleated giant cell (MNGC) formation in macrophage cell lines and is utilized as a model organism for the related and highly virulent B. pseudomallei and B. mallei, which are considered potential bioweapons [5][6][7]. Previous studies have also shown that Burkholderia infections are critically controlled by multiple inflammasomes, pyroptotic cell death, and the pyroptosisregulated inflammatory cytokine IL-18 [8][9][10]. Burkholderia infection-induced pathology is also mediated by excessive release of pyroptosis-regulated IL-1β.…”

TRAF3 promotes ROS production and pyroptosis by targeting ULK1 ubiquitination in macrophages

“…Macrophages play various roles in different stages of diseases due to their heterogeneity 6 . At the early stage of pathogens, activated macrophages release a lot of pro‐inflammatory cytokines, including interleukin (IL)‐1β and IL‐18 7,8 . Macrophages undergo inflammatory programmed cell death, called pyroptosis, at the late stage of inflammatory response under certain pathological stimulations 9‐11 .…”