Redox Regulation of the NLRP3 Inflammasome and its Implications for Immunization-related Neuroinflammation

Immunization is a critical public health intervention for limiting the impact of infectious diseases for individuals and for the population as a whole. While vaccination causes minor to moderate side effects for most, a smaller number of individuals suffer from unexpected reactogenicity and long-term effects, due to the unintended induction of an atypical inflammatory response. We hypothesize that the neurological sequelae of vaccine-induced inflammation can disproportionately affect people who have impaired cysteine status and antioxidant availability. Decreased antioxidant buffering capacity allows vaccine-induced inflammation to persist at a higher level and for a longer duration. Antioxidants are necessary to combat reactive oxygen species (ROS), produced by aerobic respiration, and when ROS levels are not effectively managed by cells, oxidative stress occurs. Oxidative stress is important for activation of the nucleotide-binding domain leucine-rich repeat [LRR] and pyrin-containing receptor 3 (NLRP3) inflammasome and its downstream consequences, including actions of the cytokine interleukin-1 beta (IL-1β). Activation of NLRP3 by oxidative stress is well appreciated, and we propose that oxidative stress from vaccines promotes NLRP3 activity and IL-1β release. This hypothesis article discusses this immunometabolic mechanistic cascade in-depth in the context of intensified short-term vaccine side effects, as well as serious inflammatory and neurological sequelae experienced by more vulnerable individuals. Research directions and alternative practices are suggested. The novel viewpoints presented here are meant to bring about changes that reduce the risk of adverse effects.