Dataset Information

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-?B) 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-1? secretion and CNS inflammation. Finally, we confirm a Nlrp3 inflammasome signature and IL-1? 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.

SUBMITTER: Voet S

PROVIDER: S-EPMC5964249 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation.

Voet Sofie S Mc Guire Conor C Hagemeyer Nora N Martens Arne A Schroeder Anna A Wieghofer Peter P Daems Carmen C Staszewski Ori O Vande Walle Lieselotte L Jordao Marta Joana Costa MJC Sze Mozes M Vikkula Hanna-Kaisa HK Demeestere Delphine D Van Imschoot Griet G Scott Charlotte L CL Hoste Esther E Gonçalves Amanda A Guilliams Martin M Lippens Saskia S Libert Claude C Vandenbroucke Roos E RE Kim Ki-Wook KW Jung Steffen S Callaerts-Vegh Zsuzsanna Z Callaerts Patrick P de Wit Joris J Lamkanfi Mohamed M Prinz Marco M van Loo Geert G

Nature communications 20180523 1

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 ...[more]

PMID: 29789522

Similar Datasets

Project description:BACKGROUND:Microglia, the mononuclear immune cells of the central nervous system (CNS), are essential for the maintenance of CNS homeostasis. BAP31, a resident and ubiquitously expressed protein of the endoplasmic reticulum, serves as a sorting factor for its client proteins, mediating the subsequent export, retention, and degradation or survival. Recently, BAP31 has been defined as a regulatory molecule in the CNS, but the function of BAP31 in microglia has yet to be determined. In the present study, we investigated whether BAP31 is involved in the inflammatory response of microglia. METHODS:This study used the BV2 cell line and BAP31 conditional knockdown mice generated via the Cre/LoxP system. A BAP31 knockdown experiment was performed to elucidate the role of BAP31 in the endogenous inflammatory cytokine production by microglial BV2 cells. A mouse model of lipopolysaccharide (LPS)-induced cognitive impairment was established to evaluate the neuroprotective effect of BAP31 against neuroinflammation-induced memory deficits. Behavioral alterations were assessed with the open field test (OFT), Y maze, and Morris water maze. The activation of microglia in the hippocampus of mice was observed by immunohistochemistry. Western blot, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and reverse transcription quantitative real-time polymerase chain reaction (RT-PCR) were used to clarify the mechanisms. RESULTS:BAP31 deficiency upregulates LPS-induced proinflammatory cytokines in BV2 cells and mice by upregulating the protein level of IRAK1, which in turn increases the translocation and transcriptional activity of NF-?B p65 and c-Jun, and moreover, knockdown of IRAK1 or use of an IRAK1 inhibitor reverses these functions. In the cognitive impairment animal model, the BAP31 knockdown mice displayed increased severity in memory deficiency accompanied by an increased expression of proinflammatory factors in the hippocampus. CONCLUSIONS:These findings indicate that BAP31 may modulate inflammatory cytokines and cognitive impairment induced by neuroinflammation through IRAK1, which demonstrates that BAP31 plays an essential role in microglial inflammation and prevention of memory deficits caused by neuroinflammation.

Dataset Information

A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation.

Publications

A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets