Nur77 attenuates Paneth cell necroptosis-induced intestinal inflammation through regulating endoplasmic reticulum homeostasis in sepsis

Sepsis, a systemic inflammatory syndrome, is frequently associated with intestinal dysfunction, which in turn exacerbates disease severity. Intestinal epithelial Paneth cells exhibit increased susceptibility to necroptosis upon inflammatory stimulation. Nuclear receptor Nur77 has been implicated in multiple programmed cell death pathways. However, the precise role of Nur77 in regulating Paneth cell necroptosis during sepsis remains unclear. This study elucidates the role and underlying molecular mechanisms of nuclear receptor Nur77 in regulating Paneth cell necroptosis during sepsis. We employed both systemic and Paneth cell-specific Nur77 knockout mouse models. Paneth cell necroptosis was assessed using TUNEL staining, immunofluorescence, and transmission electron microscopy. Endoplasmic reticulum (ER) homeostasis was evaluated based on ultrastructural integrity, ER-phagy, and ER stress. Protein modification and protein-protein interaction were validated by structure prediction and immunoprecipitation. Systemic or Paneth cell-specific Nur77 knockout exacerbated intestinal inflammation by enhancing Paneth cell necroptosis during sepsis. Nur77 deficiency in Paneth cells altered ileal microbiota rather than intestinal stem cell niche after LPS challenge. Nur77 deficiency-induced Paneth cell necroptosis was attributed to impaired ER homeostasis caused by defective ER-phagy. Mechanistically, LPS induced Nur77-PKCα interaction and their subsequent translocation to the ER, which promoted AMFR phosphorylation, FAM134B ubiquitination and subsequently ER-phagy. Treatment with Nur77 agonists (BTP and Csn-B) alleviated intestinal inflammation and restored Paneth cell homeostasis in sepsis mice. This study demonstrates that Paneth cell necroptosis plays a critical role in intestinal inflammation. Our work also identifies Nur77 as a potential therapeutic target to protect Paneth cells and maintain intestinal homeostasis during sepsis, pointing out the therapeutic potential of Nur77 agonist in sepsis.