Caspase-11 Activation in Response to Bacterial Secretion Systems that Access the Host Cytosol

Abstract

Inflammasome activation is important for antimicrobial defense because it induces cell death and regulates the secretion of IL-1 family cytokines, which play a critical role in inflammatory responses. The inflammasome activates caspase-1 to process and secrete IL-1β. However, the mechanisms governing IL-1α release are less clear. Recently, a non-canonical inflammasome was described that activates caspase-11 and mediates pyroptosis and release of IL-1α and IL-1β. Caspase-11 activation in response to Gram-negative bacteria requires Toll-like receptor 4 (TLR4) and TIR-domain-containing adaptor-inducing interferon-β (TRIF)-dependent interferon production. Whether additional bacterial signals trigger caspase-11 activation is unknown. Many bacterial pathogens use specialized secretion systems to translocate effector proteins into the cytosol of host cells. These secretion systems can also deliver flagellin into the cytosol, which triggers caspase-1 activation and pyroptosis. However, even in the absence of flagellin, these secretion systems induce inflammasome activation and the release of IL-1α and IL-1β, but the inflammasome pathways that mediate this response are unclear. We observe rapid IL-1α and IL-1β release and cell death in response to the type IV or type III secretion systems of Legionella pneumophila and Yersinia pseudotuberculosis. Unlike IL-1β, IL-1α secretion does not require caspase-1. Instead, caspase-11 activation is required for both IL-1α secretion and cell death in response to the activity of these secretion systems. Interestingly, whereas caspase-11 promotes IL-1β release in response to the type IV secretion system through the NLRP3/ASC inflammasome, caspase-11-dependent release of IL-1α is independent of both the NAIP5/NLRC4 and NLRP3/ASC inflammasomes as well as TRIF and type I interferon signaling. Furthermore, we find both overlapping and non-redundant roles for IL-1α and IL-1β in mediating neutrophil recruitment and bacterial clearance in response to pulmonary infection by L. pneumophila. Our findings demonstrate that virulent, but not avirulent, bacteria trigger a rapid caspase-11-dependent innate immune response important for host defense.

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…Caspase-11 is involved in the pyroptosis induction in LPSprimed macrophages via the type IV secretion system (T4SS) in Legionella pneumophila infection (Case et al 2013). In addition to the T4SS in L. pneumophila, the type III secretion system (T3SS) in Yersinia pseudotuberculosis is involved in caspase-11-dependent IL-1a production and cell death induction (Casson et al 2013). These results suggest that intracellular LPS and effector molecules injected via T3SS/T4SS are recognized by a cytoplasmic receptor that is yet to be identified, and activates the noncanonical inflammasome while inducing endotoxic shock.…”

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

“…Thus, Gbp Chr3 -dependent inflammasome responses to the Yersinia T3SS are driven in large part by the responses to hyperinjected YopB/YopD. canonical NLRP3 and noncanonical caspase-11 inflammasome activation (27,46). The canonical inflammasome components ASC and NLRP3 are necessary for transloconinduced release of IL-1␤ but dispensable for translocon-induced pyroptosis, which depends largely on caspase-11 (27,46).…”

“…canonical NLRP3 and noncanonical caspase-11 inflammasome activation (27,46). The canonical inflammasome components ASC and NLRP3 are necessary for transloconinduced release of IL-1␤ but dispensable for translocon-induced pyroptosis, which depends largely on caspase-11 (27,46). GBPs could thus potentially affect one or both aspects of translocon-induced inflammasome activation, as GBPs have been implicated in the activation of both canonical and noncanonical inflammasomes (31,32,59,68).…”

“…YopK-deficient Yersinia induces both a canonical NLRP3 inflammasome and a noncanonical caspase-11 inflammasome (27). Interestingly, the noncanonical inflammasome appears to be the primary pathway activated by the Yersinia translocon.…”

“…Caspase-11-dependent cleavage of GSDMD and subsequent pore formation also triggers activation of the canonical NLRP3 inflammasome by inducing potassium efflux (22)(23)(24). Caspase-11 activation can also be triggered by endocytosis of Gram-negative bacterial outer membrane vesicles (25), the activity of type III and type IV secretion systems of Gram-negative pathogens like Legionella and Yersinia (26,27), or disruption of bacterial cell-containing vacuolar compartments by members of the interferon (IFN)-inducible GTPases known as guanylate binding proteins (GBPs) (28)(29)(30)(31)(32).…”