Cutting Edge: Endoplasmic Reticulum Stress Licenses Macrophages To Produce Mature IL-1β in Response to TLR4 Stimulation through a Caspase-8-and TRIF-Dependent Pathway

The accumulation of improperly folded proteins within the endoplasmic reticulum (ER) generates perturbations known as ER stress that engage the unfolded protein response. ER stress is involved in many inflammatory pathologies that are also associated with the production of the proinflammatory cytokine IL-1 beta. In this study, we demonstrate that macrophages undergoing ER stress are able to drive the production and processing of pro-IL-1 beta in response to LPS stimulation in vitro. Interestingly, the classical NLRP3 inflammasome is dispensable, because maturation of pro-IL-1 beta occurs normally in the absence of the adaptor protein ASC. In contrast, processing of pro-IL-1 beta is fully dependent on caspase-8. Intriguingly, we found that neither the unfolded protein response transcription factors XBP1 and CHOP nor the TLR4 adaptor molecule MyD88 is necessary for caspase-8 activation. Instead, both caspase activation and IL-1 beta production require the alternative TLR4 adaptor TRIF. This pathway may contribute to IL-1-driven tissue pathology in certain disease settings.