NLRP1-Dependent Pyroptosis Leads to Acute Lung Injury and Morbidity in Mice

TLDR

Acute inflammation activates cytoplasmic inflammasomes that trigger caspase‑1, which matures cytokines and can induce pyroptotic cell death. In NLRP1‑deficient mice, anthrax toxin activates the NLRP1 inflammasome, causing caspase‑1–dependent IL‑1β release and pyroptosis that worsens over 3 days and leads to fatal acute lung injury; this effect is IL‑1β‑independent but requires caspase‑1, whereas muramyl dipeptide activates NLRP3 instead.

Abstract

Acute inflammation in response to both exogenous and endogenous danger signals can lead to the assembly of cytoplasmic inflammasomes that stimulate the activation of caspase-1. Subsequently, caspase-1 facilitates the maturation and release of cytokines and also, under some circumstances, the induction of cell death by pyroptosis. Using a mouse line lacking expression of NLRP1, we show that assembly of this inflammasome in cells is triggered by a toxin from anthrax and that it initiates caspase-1 activation and release of IL-1β. Furthermore, NLRP1 inflammasome activation also leads to cell death, which escalates over 3 d following exposure to the toxin and culminates in acute lung injury and death of the mice. We show that these events are not dependent on production of IL-1β by the inflammasome but are dependent on caspase-1 expression. In contrast, muramyl dipeptide-mediated inflammasome formation is not dependent on NLRP1 but NLRP3. Taken together, our findings show that assembly of the NLRP1 inflammasome is sufficient to initiate pyroptosis, which subsequently leads to a self-amplifying cascade of cell injury within the lung from which the lung cannot recover, eventually resulting in catastrophic consequences for the organism.