Journal of immunology (Baltimore, Md. : 1950)Apr 4, 2014

NLRP3 controls neutrophil actions and adds to liver damage after blood flow loss and return without involving inflammasomes

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Updated Apr 6, 2026

Abstract

NLRP3(-/-) mice exhibited significantly less liver injury following hepatic ischemia-reperfusion (I/R).

Hepatic I/R stimuli increased the levels of the inflammasome component NLRP3 but did not affect ASC levels.
NLRP3 deficiency resulted in reduced inflammatory responses, lower reactive oxygen species production, and decreased apoptosis in the liver after I/R.
Neutrophil infiltration into the liver during I/R was significantly inhibited in NLRP3(-/-) mice, while macrophage infiltration was unaffected.
Both bone marrow-derived and non-bone marrow-derived cells containing NLRP3 contributed to liver injury after I/R.
In vitro studies showed that NLRP3(-/-) neutrophils had impaired migration activity due to decreased activation of certain signaling pathways.

Simplified

Inflammation plays a key role in the pathophysiology of hepatic ischemia-reperfusion (I/R) injury. However, the mechanism by which hepatic I/R induces inflammatory responses remains unclear. Recent evidence indicates that a sterile inflammatory response triggered by I/R is mediated through a multiple-protein complex called the inflammasome. Therefore, we investigated the role of the inflammasome in hepatic I/R injury and found that hepatic I/R stimuli upregulated the inflammasome-component molecule, nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), but not apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). NLRP3(-/-) mice, but not ASC(-/-) and caspase-1(-/-) mice, had significantly less liver injury after hepatic I/R. NLRP3(-/-) mice showed reduced inflammatory responses, reactive oxygen species production, and apoptosis in I/R liver. Notably, infiltration of neutrophils, but not macrophages, was markedly inhibited in the I/R liver of NLRP3(-/-) mice. Bone marrow transplantation experiments showed that NLRP3 not only in bone marrow-derived cells, but also in non-bone marrow-derived cells contributed to liver injury after I/R. In vitro experiments revealed that keratinocyte-derived chemokine-induced activation of heterotrimeric G proteins was markedly diminished. Furthermore, NLRP3(-/-) neutrophils decreased keratinocyte-derived chemokine-induced concentrations of intracellular calcium elevation, Rac activation, and actin assembly formation, thereby resulting in impaired migration activity. Taken together, NLRP3 regulates chemokine-mediated functions and recruitment of neutrophils, and thereby contributes to hepatic I/R injury independently of inflammasomes. These findings identify a novel role of NLRP3 in the pathophysiology of hepatic I/R injury.

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NLRP3 controls neutrophil actions and adds to liver damage after blood flow loss and return without involving inflammasomes

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