The p38 Mitogen-Activated Protein Kinase Critically Regulates Human Keratinocyte Inflammasome Activation

Inflammasomes are key intracellular signaling platforms involved in innate immune responses to micro-organisms and danger signals. Extracellular signal-regulated kinase, Jun N-terminal kinase, and p38 mitogen-activated protein kinase family members are activated by numerous environmental stresses. Recently, it has been reported that Jun N-terminal kinase is involved in inflammasome activation in myeloid immune cells. To date, the role of mitogen-activated protein kinase in inflammasome activity in keratinocytes has not been investigated. Here, we show that, in primary human keratinocytes, p38 mitogen-activated protein kinase is required for inflammasome activation and IL-1 beta secretion. Using selective small molecule inhibitors, small interfering RNA gene silencing, and CRISPR/Cas9-based deletion, we demonstrate the above and identify p38 alpha and p38 delta as critical regulators of ASC oligomerization, inflammasome activation, and IL-1 beta secretion in keratinocytes. Furthermore, our data suggest that the nature of the mitogen-activated protein kinase regulating inflammasome activity exhibits a certain cell specificity, with p38 playing a predominant role in keratinocytes and Jun N-terminal kinase 1 in cells of myeloid origin.