The p38 mitogen-activated protein kinase critically regulates human keratinocyte inflammasome activation.

Inflammasomes are key intracellular signaling platforms involved in innate immune responses to microorganisms and danger signals. Extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) family members are activated by numerous environmental stresses. Recently, it has been reported that JNK is involved in inflammasome activation in myeloid immune cells. To date, the role of MAPK in inflammasome activity in keratinocytes has not been investigated. Here, we show that, in primary human keratinocytes, p38 MAPK is required for inflammasome activation and IL-1β secretion. Using selective small molecule inhibitors, siRNA gene silencing and CRISPR/Cas9-based deletion, we demonstrate the above and identify p38α and p38δ as critical regulators of ASC oligomerization, inflammasome activation and IL-1β secretion in keratinocytes. Furthermore, our data suggest that the nature of the MAPK regulating inflammasome activity exhibits a certain cell specificity with p38 playing a predominant role in keratinocytes and JNK1 in cells of myeloid origin.