RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD

Abstract

Necroptosis predominates functionally over apoptosis in the pathophysiology of renal ischemia-reperfusion injury (IRI). Inhibition of the core components of the necroptotic pathway—receptor-interacting protein kinase 1 (RIPK1), RIPK3 or mixed lineage kinase domain-like protein (MLKL) reduced renal injury after ischemia/reperfusion (IR). Necrosis can initiate inflammation, which enhances necrosis in a positive feedback loop, subsequently leading to triggering more inflammation, termed as necroinflammation. However, the mechanisms underlying necroinflammation driven by renal tubular cell necroptosis in progression of AKI to CKD are still largely unknown. Here we showed that the upregulated expression and interactions between RIPK3 and MLKL induced necroptosis of renal proximal tubular cells and contributed to NLRP3 inflammasome activation under the conditions of IRI. Gene deletion of Ripk3 or Mlkl ameliorated renal tubular cell necroptosis, macrophage infiltration and NLRP3 inflammasome activation with a reduction in caspase-1 activation and maturation of IL-1β, and then finally reduced interstitial fibrogenesis in the long term after IRI. Bone marrow chimeras confirmed that RIPK3-MLKL-dependent necroptosis is responsible for the initiation of the early renal injury after IRI, and then necroptosis triggered NLRP3 inflammasome activation, which subsequently accelerates necroptosis and triggers more inflammation in an auto-amplification loop. These data indicate that necroinflammation driven by RIPK3-MLKL-dependent necroptosis plays a crucial role in the progression of IRI to CKD.

Necroptosis: a crucial pathogenic mediator of human disease

“…NLRP3 inflammasome activation and IL-1β secretion were also reduced in RIPK3-or MLKL-deficient mice in response to I/R. These studies proposed a "necroinflammatory" cycle that involves reciprocal stimulation of necroptosis and NLRP3 inflammasome activation and possibly underlies the transition from AKI to chronic kidney disease (CKD) (98).…”

“…In an I/R-induced AKI model, activation of RIPK3/MLKL-dependent necroptosis was observed in renal proximal tubular epithelial cells (98). Ripk3 deficiency or kinase-deficient RIPK1 prevented I/R-dependent renal tubular cell death, inflammatory cell influx, and long-term development of fibrosis (98). NLRP3 inflammasome activation and IL-1β secretion were also reduced in RIPK3-or MLKL-deficient mice in response to I/R.…”

Inhibition of microglial receptor‐interacting protein kinase 1 ameliorates neuroinflammation following cerebral ischaemic stroke

“…It has been reported that RIPK1 can trigger the activation of the NLRP3 inflammasome by disrupting the mitochondrial membrane integrity and by promoting the release of ROS, which further promotes the production and secretion of IL‐1β to the extracellular space and initiates neuroinflammation. Furthermore, the activation of RIPK3‐MLKL can directly trigger the activation of the NLRP3 inflammasome 11,42 . To investigate the role of rhTrx‐1 in RIPK1‐induced NLRP3 inflammasome activation in ischaemic microglia, we examined the levels of NLRP3, ASC and cleaved‐caspase‐1 and indicated that rhTrx‐1 ultimately reduced the release of IL‐1β, depending on the inhibition of the NLRP3 inflammasome.…”

RhTrx-1 ameliorates miroglial neuroinflammation after cerebral ischemic stroke

“…It has been reported that the activation of RIPK3-MLKL can directly trigger the activation of NLRP3 inflammasome in renal tubular cells [39]. Furthermore, RIPK1 can trigger the activation of NLRP3 inflammasome by destroying mitochondria membrane and promoting the release of ROS, which further promotes the production and secretion of IL-1β to extracellular and initiate neuroinflammation.…”