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Am J Physiol Lung Cell Mol Physiol ; 316(3): L418-L427, 2019 03 01.
Article in English | MEDLINE | ID: mdl-30628485

ABSTRACT

We previously showed that mice deficient in apoptosis signal-regulating kinase-1 (ASK1) were partially protected against ventilator-induced lung injury. Because ASK1 can promote both cell death and inflammation, we hypothesized that ASK1 activation regulates inflammasome-mediated inflammation. Mice deficient in ASK1 expression (ASK1-/-) exhibited significantly less inflammation and lung injury (as measured by neutrophil infiltration, IL-6, and IL-1ß) in response to treatment with inhaled lipopolysaccharide (LPS) compared with wild-type (WT) mice. To determine whether this proinflammatory response was mediated by ASK1, we investigated inflammasome-mediated responses to LPS in primary macrophages and bone marrow-derived macrophages (BMDMs) from WT and ASK1-/- mice, as well as the mouse alveolar macrophage cell line MH-S. Cells were treated with LPS alone for priming or LPS followed by ATP for activation. When macrophages were stimulated with LPS followed by ATP to activate the inflammasome, we found a significant increase in secreted IL-1ß from WT cells compared with ASK1-deficient cells. LPS priming stimulated an increase in NOD-like receptor 3 (NLRP3) and pro-IL-1ß in WT BMDMs, but expression of NLRP3 was significantly decreased in ASK1-/- BMDMs. Subsequent ATP treatment stimulated an increase in cleaved caspase-1 and IL-1ß in WT BMDMs compared with ASK1-/- BMDMs. Similarly, treatment of MH-S cells with LPS + ATP caused an increase in both cleaved caspase-1 and IL-1ß that was diminished by the ASK-1 inhibitor NQDI1. These results demonstrate, for the first time, that ASK1 promotes inflammasome priming.


Subject(s)
Apoptosis/drug effects , Inflammasomes/drug effects , MAP Kinase Kinase Kinase 5/metabolism , Macrophages/drug effects , Animals , Carrier Proteins/metabolism , Cell Line , Inflammasomes/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides/pharmacology , MAP Kinase Kinase Kinase 5/drug effects , Macrophages/metabolism , Mice, Inbred C57BL , Mice, Knockout , Neutrophil Infiltration/drug effects , Signal Transduction/drug effects
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