Human Monocytes Engage an Alternative Inflammasome Pathway

Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an “alternative inflammasome” that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K+ efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1β-mediated immune responses and immunopathology in humans. [Display omitted] •LPS by itself triggers IL-1β secretion in human, but not in murine monocytes•Human monocytes activate an alternative inflammasome in response to LPS•This proceeds independently of K+ efflux, pyroptosome formation, and pyroptosis•Alternative but not classical inflammasome signals via TLR4-TRIF-RIPK1-FADD-CASP8 How human monocytes secrete processed IL-1β upon LPS challenge is unknown. Hornung and colleagues report that LPS triggers an alternative NLRP3 inflammasome pathway in human monocytes. Unlike classical NLRP3 inflammasome signaling, alternative inflammasome activation proceeds independently of potassium efflux, pyroptosome formation, and pyroptosis, while it engages TLR4-TRIF-RIPK1-FADD-CASP8 upstream of NLRP3.