Caspase-1-Deficient Mice Have Delayed Neutrophil Apoptosis and a Prolonged Inflammatory Response to Lipopolysaccharide-Induced Acute Lung Injury

Abstract

Caspase-1, the prototypic caspase, is known to process the cytokines IL-1β and IL-18 to mature forms but it is unclear whether, like other caspases, it can induce apoptosis by activation of downstream protease cascades. Neutrophils are known to express caspase-1, to release IL-1β and to undergo rapid, caspase-dependent apoptosis. We examined apoptosis and IL-1β production in peripheral blood neutrophils of caspase-1-deficient and wild-type mice. Constitutive apoptosis of caspase-1-deficient neutrophils was delayed compared with wild-type neutrophils and LPS-mediated inhibition of apoptosis was absent, but caspase-1-deficient neutrophils were susceptible to Fas-mediated apoptosis. LPS-stimulated IL-1β production was absent from caspase-1-deficient neutrophils. To ascertain whether these differences in apoptosis and IL-1β production would alter the response to acute lung injury, we studied pulmonary neutrophil accumulation following intratracheal administration of LPS. Caspase-1-deficient mice showed increased, predominantly neutrophilic pulmonary inflammation, but inflammation had resolved in both wild-type and deficient animals by 72 h after LPS instillation. IL-1β production was increased in wild-type lungs but was also detected in caspase-1-deficient mice. We conclude that caspase-1 modulates apoptosis of both peripheral blood and inflammatory neutrophils, but is not essential for IL-1β production in the lung.

Inhibition of neutrophil apoptosis by PAI-1

“…Exposure of neutrophils to TNF-related apoptosis-inducing ligand (TRAIL) resulted in enhanced apoptosis (Fig. 6F), consistent with previous studies showing the importance of extrinsic induced apoptotic pathways in neutrophil death (27,31,41). Inclusion of PAI-1 in the neutrophil cultures diminished the proapoptotic effects of TRAIL (Fig.…”

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

“…(33,34) As expected, LPS-treated neutrophils showed higher expression of NF-κB pathway genes compared with nontreated controls and A1AT-treated cells. Concomitantly, we observed a several-fold increase in IL-1β precursor and supernatant levels of IL-1β.…”

“…(39) Thus, in neutrophils, LPS alone can upregulate caspase-1 and generate a release of small amounts of IL-1β. (34,56,57) Therefore, we next investigated NLRP3 inflammasome components in neutrophils stimulated with LPS compared with neutrophils treated with LPS and A1AT combinations. The mRNA and protein expression of NLRP3 and CASP1 increased following LPS treatment as compared with cells not Figure 8.…”

Ways of dying: multiple pathways to apoptosis

“…When caspase-11 is induced by lipopolysaccharide (as is human caspase-5), it contributes to the activation of caspase-3 and caspase-7 as well as caspase-1 (Kang et al 2002), and caspase-1 can also process the executioner caspases in vitro ( Van de Craen et al 1999). Furthermore, oligodendrocytes lacking caspase-11 are somewhat refractory to cytotoxic cytokines (Hisahara et al 2001), neutrophils lacking caspase-1 die more slowly in culture (Rowe et al 2002) and, as noted above, dying Apaf-1-null hematopoietic cells contain active caspase-1 .…”