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

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 three days 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, MDP 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.

Uromodulin, Inflammasomes, and Pyroptosis

“…15,16 Consistent with the hypothesis advanced by Darisipudi et al of an injurious role of inflammasome activation by uromodulin, toxin-induced pyroptosis may promote tissue injury, as shown for the lung. 15 However, the role of pyroptosis in kidney injury or in sterile inflammation has not been well characterized.…”

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

“…Cx3cr1 GFP mice (JAX5582) in which the Cx3cr1 gene is replaced with the GFP reporter gene (37), Nlrp3 knockout (Nlrp3 Δ ) mice (JAX21302) in which the entire coding region of Nlrp3 is replaced with neomycin resistance gene (58), and C57BL/6J wild-type mice (JAX664) were purchased from the Jackson Laboratory to establish colonies in our animal facility. Cx3cr1 GFP mice, on a mixed C57BL/6J; C57BL/6N genetic background, were crossed with wild-type C57BL/6J mice to generate Cx3cr1 GFP/+ mice.…”

Guanylate Binding Proteins Enable Rapid Activation of Canonical and Noncanonical Inflammasomes in Chlamydia-Infected Macrophages

“…Ϫ/Ϫ , and Casp1 Ϫ/Ϫ Casp11 Ϫ/Ϫ mice were previously described (25)(26)(27)(28)(29)(30)(31)(32)(33). BMMs were cultured in RPMI 1640 supplemented with 2-mercaptoethanol, 20% FBS, and 14% conditioned media containing macrophage colony-stimulating factor.…”