Apoptosis signal-regulating kinase-1 promotes inflammasome priming in macrophages

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.

TRAF3 promotes ROS production and pyroptosis by targeting ULK1 ubiquitination in macrophages

“…Macrophages undergo inflammatory programmed cell death, called pyroptosis, at the late stage of inflammatory response under certain pathological stimulations 9‐11 . Macrophages primed by TLR agonists followed by nigericin or ATP stimulation induces the formation of inflammasome and accelerate pyroptotic cell death 12,13 . The pyroptotic cells are characterized as mature caspase 1 production and propidium iodide (PI)‐positive staining 14 .…”

Exploring the Mechanism of Bergamot Essential Oil against Asthma Based on Network Pharmacology and Experimental Verification

“…MH-S were cultured in 1640 medium (Gibco, New York) with 10% fetal bovine serum (FBS) (Gibco, New York) at 37 °C and 5% CO 2 in an incubator. The inflammation model was induced using LPS (Sigma, St. Louis, MO, 0.1 mg/mL). , …”

“…The inflammation model was induced using LPS (Sigma, St. Louis, MO, 0.1 mg/mL). 60,61 5.10. BEO Toxicity Test.…”

MicroRNA‐23a‐5p Is Involved in the Regulation of Lipopolysaccharide‐Induced Acute Lung Injury by Targeting HSP20/ASK1

“…As shown in Figures 7(a 3.12. miR-23a-5p Agomir Activates ASK1 via Directly Reducing HSP20 Expression. Previous studies have reported that HSP20 is required for ASK1 inhibition and that HSP20 protects against LPS-induced organic injury, including ALI [8,9,56]. Herein, we identified two potential binding sites in the 3′ UTR of HSP20 using the online TargetScan software (Figure 9(a)).…”

“…Immanuel et al found that ASK1 promoted NLRP3 inflammasome priming in macrophages, thereby aggravating the proinflammatory response. Conversely, ASK1-deficient mice had significantly less inflammation and lung injury upon lipopolysaccharide (LPS) inhalation [ 9 ]. Besides, ASK1 deletion also decreased hyperoxia-induced inflammation, oxidative stress, and pulmonary dysfunction in mice [ 10 ].…”