The Rate of Interleukin-1β Secretion in Different Myeloid Cells Varies with the Extent of Redox Response to Toll-like Receptor Triggering

Human myeloid cells activate the NLRP3 inflammasome and secrete interleukin (IL)-1 beta in response to various Toll-like receptor (TLR) ligands, but the rate of secretion is much higher in primary human monocytes than in cultured macrophages or THP-1 cells. The different myeloid cells also display different redox status under resting conditions and redox response to TLR activation. Resting monocytes display a balanced redox state, with low production of reactive oxygen species (ROS) and antioxidants. TLR engagement induces an effective redox response with increased ROS generation followed by a sustained antioxidant response, parallelled by efficient IL-1 beta secretion. Drugs blocking ROS production or the antioxidant response prevent the secretion of mature IL-1 beta but not the biosynthesis of pro-IL-1 beta, indicating that redox remodeling is responsible for IL-1 beta processing and release. Unlike monocytes, THP-1 cells and cultured macrophages have up-regulated antioxidant systems that buffer the oxidative hit provided by TLR triggering and suppress the consequent redox response. This aborted redox remodeling is paralleled by low efficiency IL-1 beta processing and secretion. High doses (5mM) of H2O2 overcome the high antioxidant capacity of THP-1 cells, restore an efficient redox response, and increase the rate of IL-1 beta secretion. Together these data indicate that a tightly controlled redox homeostasis in resting cells is a prerequisite for a robust redox response to TLR ligands, in turn necessary for the efficient inflammasome activation. Inflammasome activation by bacterial DNA is not modulated by redox responses, suggesting that redox-dependent regulation of IL-1 beta secretion is restricted to some inflammasomes including NLRP3 but excluding AIM-2.