Lipocalin 2 deficiency attenuates NLRP3 inflammasome activation through glycolysis impairment and MGST1-mediated...

Lipocalin 2 (Lcn2), a multifunctional innate immune protein, plays a critical role in many biological processes, especially in mediating inflammation. However, its role in the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome remains elusive. In this study, we generated whole-body Lcn2-knockout mice and demonstrated that Lcn2 deficiency reduced the secretion of interleukin (IL)-1β and IL-18 in murine models of sepsis, gouty arthritis and colitis. Using Lcn2-deficient bone marrow-derived macrophages (BMDMs), we showed that Lcn2 deficiency mostly inhibited the inflammatory response by modifying transcriptional priming and posttranslational activation of NLRP3 inflammasome. At the transcriptional level, Lcn2-deficient BMDMs exhibited reduced priming of the NLRP3 inflammasome, as provided by decreased activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), alongside diminished transcription of NLRP3 and IL-1β. At the posttranslational level, Lcn2 deficiency attenuated NLRP3 inflammasome activation by reducing glycolytic activity and mitochondrial reactive oxygen species (mt-ROS) production. Furthermore, upregulation of microsomal glutathione S-transferase 1 (MGST1) in Lcn2-deficient BMDMs mitigated NLRP3 inflammasome activation by suppressing mt-ROS accumulation. Collectively, these findings uncover Lcn2 as an important mediator of inflammatory responses and it could be a prospective target for treating NLRP3-associated inflammatory disorders.