Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila

Abstract

A flagellin-independent caspase-1 activation pathway that does not require NAIP5 or NRLC4 is induced by the intracellular pathogen Legionella pneumophila. Here we demonstrate that this pathway requires caspase-11. Treatment of macrophages with LPS up-regulated the host components required for this caspase-11 activation pathway. Activation by Legionella differed from caspase-11 activation using previously described agonists in that Legionella caspase-11 activation was rapid and required bacteria with a functional type IV secretion system called Dot/Icm. Legionella activation of caspase-11 induced pyroptosis by a mechanism independent of the NAIP/ NLRC4 and caspase-1 axis. Legionella activation of caspase-11 stimulated activation of caspase-1 through NLRP3 and ASC. Induction of caspase-11-dependent responses occurred in macrophages deficient in the adapter proteins TRIF or MyD88 but not in macrophages deficient in both signaling factors. Although caspase-11 was produced in macrophages deficient in the type-I IFN receptor, there was a severe defect in caspase-11-dependent pyroptosis in these cells. These data indicate that macrophages respond to microbial signatures to produce proteins that mediate a capsase-11 response and that the caspase-11 system provides an alternative pathway for rapid detection of an intracellular pathogen capable of evading the canonical caspase-1 activation system that responds to bacterial flagellin.innate immunity | cell death | inflammasome

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

“…During L. pneumophila infection of murine macrophages, activation of the inflammasome occurs through NAIP5/NLRC4, triggered by flagellin, as well as through an apoptosis-associated speck-like protein containing a CARD (ASC)-dependent pathway, resulting in the production of cytokines via an IL-1 autocrine loop (22,23,(53)(54)(55)(56). Humans lack the NAIP5 allele present in murine cells (57); however, the canonical ASC-dependent inflammasome is still activated upon L. pneumophila infection of human macrophages (58).…”

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…Furthermore, bacterial secretion systems to translocate effector proteins such as flagellin into host cells are involved in the activation of caspase-11. 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).…”

Guanylate binding proteins promote caspase-11–dependent pyroptosis in response to cytoplasmic LPS

“…Accordingly, an L. pneumophila mutant that aberrantly enters the cytosol, ΔsdhA, was shown to initiate a rapid caspase-11 response in naive macrophages (12). Rapid, flagellin-independent activation of caspase-11 is also observed in macrophages infected with sdhA + L. pneumophila strains, but only if macrophages were primed with stimuli, such as external LPS (10). The caspase-11 response observed in LPS-primed macrophages infected with flagellin-deficient (ΔflaA), sdhA + L. pneumophila requires cofactors that are IFN-inducible (10).…”

“…In addition to the canonical inflammasome pathway induced by cytoplasmic flagellin, L. pneumophila infections can trigger a flagellin-independent, noncanonical inflammasome pathway defined by the activation of caspase-11 (10,11). Activated caspase-11 promotes rapid cell death independent of caspase-1 and independent of any known components of canonical inflammasomes (12,13).…”