Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to <i>Legionella pneumophila</i>

TLDR

A flagellin‑independent caspase‑1 activation pathway that does not require NAIP5 or NLRC4 is induced by the intracellular pathogen Legionella pneumophila. The study demonstrates that this pathway requires caspase‑11. Treatment of macrophages with LPS up‑regulates the host components necessary for caspase‑11 activation. Legionella triggers rapid, Dot/Icm‑dependent caspase‑11 activation that induces pyroptosis independently of NAIP/NLRC4 and caspase‑1, also activating caspase‑1 via NLRP3/ASC, and this response persists in TRIF/MyD88‑deficient macrophages but is impaired by type‑I IFN receptor deficiency, demonstrating caspase‑11 as an alternative rapid detection pathway.

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.