A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation

Abstract

Microglia, the mononuclear phagocytes of the central nervous system (CNS), are important for the maintenance of CNS homeostasis, but also critically contribute to CNS pathology. Here we demonstrate that the nuclear factor kappa B (NF-κB) regulatory protein A20 is crucial in regulating microglia activation during CNS homeostasis and pathology. In mice, deletion of A20 in microglia increases microglial cell number and affects microglial regulation of neuronal synaptic function. Administration of a sublethal dose of lipopolysaccharide induces massive microglia activation, neuroinflammation, and lethality in mice with microglia-confined A20 deficiency. Microglia A20 deficiency also exacerbates multiple sclerosis (MS)-like disease, due to hyperactivation of the Nlrp3 inflammasome leading to enhanced interleukin-1β secretion and CNS inflammation. Finally, we confirm a Nlrp3 inflammasome signature and IL-1β expression in brain and cerebrospinal fluid from MS patients. Collectively, these data reveal a critical role for A20 in the control of microglia activation and neuroinflammation.

Control of the inflammasome by the ubiquitin system

“…A recent report has shown that A20 prevents inflammasomedependent arthritis through its ZnF7 ubiquitin-binding domain. As just discussed [59][60][61], this work showed that A20-deficient mice (A20 myc KO ) developed spontaneous arthritis that is critically dependent on RIPK1-RIPK3-MLKL-mediated necroptosis and that was accompanied by IL-1b and TNF-a release. Further studies on BMDMs further revealed that IL-1b release was mediated by RIPK3-dependent cell death (necroptosis) and that ZnF7 is critical for this function as LPS stimulation of BMDMs from mice with a mutated ZnF7 domain (A20 mZnF7/mZnF7 ) also induces the release of processed IL-1b (although at lower levels compared with A20-knockout cells) [63].…”

Inflammasomes in neuroinflammatory and neurodegenerative diseases

“…Interestingly, IFNβ, the first line treatment for MS, is only effective in an NLRP3 inflammasome‐dependent EAE subtype, whereas NLRP3‐independent EAE could not be reversed by IFN‐β therapy (Inoue et al , , ). We recently provided direct genetic evidence for the relevance of inflammasome signaling in microglia and border‐associated macrophages during EAE (Voet et al , ). The anti‐inflammatory protein A20 has been shown to negatively regulate NLRP3 inflammasome activation (Vande Walle et al , ), and deletion of A20 in microglia and CNS macrophages exacerbated EAE in mice due to NLRP3 hyperactivation that resulted in increased IL‐1β secretion and CNS inflammation (Voet et al , ).…”

“…We recently provided direct genetic evidence for the relevance of inflammasome signaling in microglia and border‐associated macrophages during EAE (Voet et al , ). The anti‐inflammatory protein A20 has been shown to negatively regulate NLRP3 inflammasome activation (Vande Walle et al , ), and deletion of A20 in microglia and CNS macrophages exacerbated EAE in mice due to NLRP3 hyperactivation that resulted in increased IL‐1β secretion and CNS inflammation (Voet et al , ). CNS‐intrinsic inflammasome activation was further reported in another study that showed caspase‐1‐ and GSDMD‐mediated pyroptosis in microglia, as well as in myelin‐forming oligodendrocytes in the CNS of MS patients and EAE mice (Mckenzie et al , ).…”

“…Caspase-1, IL-18, and IL-1b are upregulated in peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) of MS patients, as are levels of the NLRP3 inflammasome-activating DAMPs ATP and uric acid (Inoue & Shinohara, 2013;Mamik & Power, 2017). Moreover, caspase-1 expression was shown to be elevated in acute and chronic demyelinating lesions (Voet et al, 2018), and caspase-1 and ASC have recently been proposed as candidate biomarkers for MS onset (Keane et al, 2018).…”

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

“…A20 deubiquitinase, a negative regulator of NF‐κB, has been reported to play a critical role in activation of microglia and inhibition of inflammasome‐dependent neuroinflammation through blocking ubiquitination of pro‐IL‐1β . However, A20 does not effectively inhibit other inflammasomes, such as AIM2 and NLRC4 .…”