Induced pluripotent stem cell-derived macrophages enable broad modeling of human inflammasome signaling

Macrophage models are a mainstay of inflammasome research; however, current in vitro models have significant limitations. Here, we generate induced pluripotent stem cell (iPSC)-derived macrophages (iMacs) to study inflammasome signaling and benchmark them with human monocyte-derived macrophages. We confirm that iMacs express high levels of macrophage markers and are highly phagocytic. Proteomic analysis shows iMacs express many inflammasome sensors and related proteins, and iMacs respond to multiple inflammasome stimuli. The NLRP3 inflammasome is strongly activated in iMacs, and nigericin alone activates NLRP3. The non-canonical inflammasome does not require a priming step, and high NAIP/NLRC4 activation is observed in response to needle toxin. Finally, unlike human monocyte-derived macrophages (HMDMs), talabostat activates NLRP1 in iMacs. Therefore, we demonstrate that iMacs are a physiologically relevant and attractive model to study inflammasome signaling.