Novel role of Hippo effector YAP1 as a rheostat controlling inflammation in dendritic cells

Abstract Dendritic cells (DCs) function within tissues that experience wide fluctuations in oxygen availability, and these hypoxic environments exert a strong influence on innate immune activity. In this context, we identify the Hippo pathway effector YAP1 as a central regulator of human monocyte-derived DC responses under low-oxygen conditions. YAP1 is expressed in DCs and undergoes dynamic modulation following LPS stimulation, affecting signaling processes in both the cytoplasm and nucleus. Loss of YAP1 function—through pharmacological inhibition or gene knockdown—amplifies reactive oxygen species (ROS) accumulation during hypoxia and drives robust activation of the p38 MAPK pathway, resulting in increased IL-1β expression. In contrast, stabilization of YAP1 using a phosphorylation-resistant S366A mutant enhances transcription of IL-6 and TNF-α, maintains activation of p38, NF-κB, and ERK pathways, and augments IL-1β release through a cytokine-dependent autocrine loop. Together, these findings position YAP1 as a homeostatic rheostat that balances DC inflammatory responses in hypoxic environments. By limiting oxidative-stress–induced inflammation while simultaneously supporting cytokine-driven amplification of immune signaling, YAP1 provides a mechanism through which DCs integrate environmental and inflammatory cues. This dual regulatory role highlights YAP1 as an important mediator of innate immune adaptation to tissue hypoxia. Moreover, understanding how YAP1 shapes DC function offers new insight into the mechanisms underlying inflammatory and autoimmune disease pathogenesis, where dysregulated oxygen sensing and cytokine production contribute to chronic immune activation.