NLRP3 Attenuates Intraocular Inflammation by Inhibiting AIM2 Mediated Pyroptosis Through the SIK1/SREBF1 Pathway

Abstract

The NLRP3 inflammasome has been shown to be involved in the development of uveitis, but the exact mechanism remains elusive. Here, we explored the role of NLRP3 in the development of uveitis. Surprisingly, contrary to previous studies, our results show that NLRP3 plays an anti-inflammatory role in two models of experimental autoimmune disease, such as experimental autoimmune uveitis (EAU) and experimental autoimmune encephalomyelitis (EAE), and reduces macrophage infiltration during EAU. Additionally, macrophages show an increased pyroptosis in Nlrp3-/- mice. Further experiments indicate that this pyroptosis of macrophages was mediated by the upregulated transcription of Aim2 as a result of Nlrp3 deficiency. In mechanistic studies, Nlrp3 deficiency was implicated in downregulation of p-SIK1 and subsequently the upregulation of SREBF1, which binds to Aim2 and then promotes the latter’s transcription. Finally, RNA silencing of Aim2 or Srebf1 and induced overexpression of Nlrp3 resulted in an attenuated inflammation of EAU. In summary, our data show that NLRP3 inhibits Aim2 inflammasome mediated EAU by regulating the expression of SREBF1, highlighting the therapeutic potential of targeting Nlrp3.