Mitophagy: a balance regulator of NLRP3 inflammasome activation

Abstract

The NLRP3 inflammasome is activated by a variety of external or host-derived stimuli and its activation initiates an inflammatory response through caspase-1 activation, resulting in inflammatory cytokine IL-1β maturation and secretion. The NLRP3 inflammasome activation is a kind of innate immune response, most likely mediated by myeloid cells acting as a host defense mechanism. However, if this activation is not properly regulated, excessive inflammation induced by overactivated NLRP3 inflammasome can be detrimental to the host, causing tissue damage and organ dysfunction, eventually causing several diseases. Previous studies have suggested that mitochondrial damage may be a cause of NLRP3 inflammasome activation and autophagy, which is a conserved self-degradation process that negatively regulates NLRP3 inflammasome activation. Recently, mitochondria-selective autophagy, termed mitophagy, has emerged as a central player for maintaining mitochondrial homeostasis through the elimination of damaged mitochondria, leading to the prevention of hyperinflammation triggered by NLRP3 inflammasome activation. In this review, we will first focus on the molecular mechanisms of NLRP3 inflammasome activation and NLRP3 inflammasome-related diseases. We will then discuss autophagy, especially mitophagy, as a negative regulator of NLPP3 inflammasome activation by examining recent advances in research. [BMB Reports 2016; 49(10): 529-535]

Metformin upregulates mitophagy in patients with T2DM: A randomized placebo‐controlled study

“…Previous studies have reported that mitophagy negatively regulates inflammasome activation and metformin treatment decreases the expression of NLRP3, caspase‐1 and IL‐β in NDT2DM patients . However, our data appeared inconsistent with prior studies and revealed that metformin therapy led to augmented NLRP3 protein expression in these patients, which may subsequently trigger caspase‐1‐mediated pyroptosis of chronically activated macrophages, and thereby impeding chronic inflammation (Figure ).…”

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

“…Mitophagy, a mitochondria‐specific autophagy pathway, has been reported to be a negative regulator of NLRP3 inflammasome‐mediated hyperinflammation . Mounting evidence suggests that mitophagy and disruption of mitochondrial dynamics directly contribute to dopaminergic neuronal cell death in PD .…”

ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination

“…However, there is still a lack of drugs that directly interfere with NLRP3 inflammasome activation in clinical treatment. In addition, in LPS-primed macrophages, the interaction between endogenous ABRO1 and NLRP3 disappeared upon nigericin or ATP stimulation, implying that this key molecular mechanism of NLRP3 deubiquitination mediated by ABRO1 may contribute to the self-limiting regulation of inflammasome activation (Kim et al, 2016). Importantly, various DUBs are emerging as attractive therapeutic targets in diseases ranging from oncology to neurodegeneration, and firstgeneration DUB inhibitors are now approaching clinical trials (Harrigan et al, 2018).…”