| First Author | Immanuel CN | Year | 2019 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 316 |
| Issue | 3 | Pages | L418-L427 |
| PubMed ID | 30628485 | Mgi Jnum | J:272108 |
| Mgi Id | MGI:6280203 | Doi | 10.1152/ajplung.00199.2018 |
| Citation | Immanuel CN, et al. (2019) Apoptosis signal-regulating kinase-1 promotes inflammasome priming in macrophages. Am J Physiol Lung Cell Mol Physiol 316(3):L418-L427 |
| abstractText | 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-1beta) 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-1beta from WT cells compared with ASK1-deficient cells. LPS priming stimulated an increase in NOD-like receptor 3 (NLRP3) and pro-IL-1beta 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-1beta 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-1beta that was diminished by the ASK-1 inhibitor NQDI1. These results demonstrate, for the first time, that ASK1 promotes inflammasome priming. |
