Blockade of IKK signaling induces RIPK1-independent apoptosis in human cells

Abstract

ABSTRACTRegulated cell death in response to microbial infection plays an important role in immune defense and is triggered by pathogen disruption of essential cellular pathways. Gramnegative bacterial pathogens in theYersiniagenus disrupt NF-κB signaling via translocated effectors injected by a type III secretion system (T3SS), thereby preventing induction of cytokine production and antimicrobial defense. In murine models of infection,Yersiniablockade of NF-κB signaling triggers cell-extrinsic apoptosis through Receptor Interacting Serine-Threonine Protein Kinase 1 (RIPK1) and caspase-8, which is required for bacterial clearance and host survival. Unexpectedly, we find that human macrophages undergo apoptosis independently of RIPK1 in response toYersiniaor chemical blockade of IKKα/β. Instead, IKK blockade led to decreased cFLIP expression, and overexpression of cFLIP contributed to protection from IKK blockade-induced apoptosis in human macrophages. Importantly, IKK blockade also induces RIPK1 kinase-independent apoptosis in human T cells and human pancreatic cells. Altogether, our data indicate that, in contrast to murine cells, blockade of IKK activity in human cells triggers a distinct apoptosis pathway that is independent of RIPK1. These findings have implications for the contribution of RIPK1 to cell death in humans and the efficacy of RIPK1 inhibition in human diseases.