The TXNIP-NLRP3 pathway modulates sleep responses to muramyl dipeptide and lipopolysaccharide in mice 2992

Abstract Description In multiple species, interleukin-1 beta (IL-1β) and the bacterial cell wall components muramyl dipeptide (MDP) and lipopolysaccharide (LPS) can increase non-rapid eye movement (NREM) sleep and alter slow-wave activity (SWA) when applied centrally or to the periphery. We previously found that NLRP3 inflammasomes, which activate the mature form of IL-1β, were critical to mediating NREM sleep and SWA responses to LPS. Evidence suggests that TXNIP is required for NLRP3 inflammasome activation. Herein, we determined the effects of suppressing TXNIP with a short hairpin RNA adeno-associated virus vector (AAV) and overexpressing TXNIP with an AAV on sleep and molecular activation of the TXNIP-NLRP3 inflammasome pathway after MDP and LPS were applied centrally to C57BL/6J mice. Compared to controls, enhanced NREM sleep and SWA responses in the first 6 hours after administration of both MDP and LPS were significantly attenuated with shRNA but were significantly greater and lasted for 12 hours after administration in the TXNIP overexpressing AAV group. Gene expression and protein levels of TXNIP, NLRP3, and IL-1β showed similar patterns consistent with shRNA attenuating TXNIP-NLRP3 inflammasome activation and the overexpression TXNIP AAV exacerbating TXNIP-NLRP3 inflammasome activation after MDP and LPS administration. These data suggest that TXNIP-NLRP3 pathway regulates NREM sleep and SWA responses to Gram-negative and Gram-positive bacteria. Funding Sources Supported by Veterans Affairs Merit Review Award I01BX005379 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)