Title: Apoptosis signal-regulating kinase-1 promotes inflammasome priming in macrophages.
Authors: Immanuel, Camille N; Teng, Bin; Dong, Brittany; Gordon, Elizabeth M; Kennedy, Joseph A; Luellen, Charlean; Schwingshackl, Andreas; Cormier, Stephania A; Fitzpatrick, Elizabeth A; Waters, Christopher M
Published In Am J Physiol Lung Cell Mol Physiol, (2019 03 01)
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-1β) 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-1β from WT cells compared with ASK1-deficient cells. LPS priming stimulated an increase in NOD-like receptor 3 (NLRP3) and pro-IL-1β 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-1β 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-1β that was diminished by the ASK-1 inhibitor NQDI1. These results demonstrate, for the first time, that ASK1 promotes inflammasome priming.
PubMed ID: 30628485
MeSH Terms: Animals; Apoptosis/drug effects*; Carrier Proteins/metabolism; Cell Line; Inflammasomes/drug effects*; Inflammasomes/metabolism; Inflammation/drug therapy; Inflammation/metabolism; Lipopolysaccharides/pharmacology; MAP Kinase Kinase Kinase 5/drug effects; MAP Kinase Kinase Kinase 5/metabolism*; Macrophages/drug effects*; Macrophages/metabolism; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration/drug effects; Signal Transduction/drug effects