Granzyme A Produces Bioactive IL-1β through a Nonapoptotic Inflammasome-Independent Pathway

• PMT triggers IL-1β transcription through RhoA/ROCK-activated NF-кB
• Granzyme A is expressed in macrophages through STAT activation
• Granzyme A cleaves IL-1β intracellularly into bioactive IL-1β
• PMT stimulates IL-1β maturation through an inflammasome-independent pathway

SummaryBacterial components are recognized by the immune system through activation of the inflammasome, eventually causing processing of the proinflammatory cytokine interleukin-1β (IL-1β), a pleiotropic cytokine and one of the most important mediators of inflammation, through the protease caspase-1. Synthesis of the precursor protein and processing into its bioactive form are tightly regulated, given that disturbed control of IL-1β release can cause severe autoinflammatory diseases or contribute to cancer development. We show that the bacterial Pasteurella multocida toxin (PMT) triggers Il1b gene transcription in macrophages independently of Toll-like receptor signaling through RhoA/Rho-kinase-mediated NF-κΒ activation. Furthermore, PMT mediates signal transducer and activator of transcription (STAT) protein-controlled granzyme A (a serine protease) expression in macrophages. The exocytosed granzyme A enters target cells and mediates IL-1β maturation independently of caspase-1 and without inducing cytotoxicity. These findings show that macrophages can induce an IL-1β-initiated immune response independently of inflammasome activity.

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