A20 expression in dendritic cells protects mice from LPS‐induced mortality

Xuân, Nguyễn Thị; Wang, Xu; Nishanth, Gopala; Waisman, Ari; Borucki, Katrin; Isermann, Berend; Naumann, Michael; Deckert, Martina; Schlüter, Dirk

doi:10.1002/eji.201444795

Cited by 29 publications

(38 citation statements)

References 40 publications

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“…This may be explained by the fact that cytokine production of CD4 + (IFN-γ, IL-2) and CD8 + T cells (IFN-γ, granzyme B) was not increased in naïve CD4-Cre as compared to A20 fl/fl mice. This is in contrast to mouse strains with deletion of A20 in B cells, dendritic cells and macrophages, respectively, which all develop severe spontaneous inflammatory diseases2324252645 and indirectly argues for a specific deletion of A20 in T cells of CD4-Cre A20 fl/fl mice.…”

Section: Discussionmentioning

confidence: 88%

“…A20 fl/fl mice on a C57BL/6 background as described before were crossed with CD4-Cre mice to obtain CD4-Cre A20 fl/fl mice25. Genotyping was done by PCR of tail DNA with primers for CD4-Cre and A20 fl/fl .…”

Section: Methodsmentioning

confidence: 99%

“…In addition, selective deletion of A20 in dendritic cells232425, myeloid cells26, B cells272829, and astrocytes20 respectively, results in or exacerbates autoimmunity. In humans, polymorphisms of the A20-encoding Tnfaip3 gene predisposes to numerous diseases including autoimmune disorders30.…”

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confidence: 99%

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A20 Curtails Primary but Augments Secondary CD8+ T Cell Responses in Intracellular Bacterial Infection

Just

Nishanth

Buchbinder

et al. 2016

Sci Rep

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The ubiquitin-modifying enzyme A20, an important negative feedback regulator of NF-κB, impairs the expansion of tumor-specific CD8+ T cells but augments the proliferation of autoimmune CD4+ T cells. To study the T cell-specific function of A20 in bacterial infection, we infected T cell-specific A20 knockout (CD4-Cre A20fl/fl) and control mice with Listeria monocytogenes. A20-deficient pathogen-specific CD8+ T cells expanded stronger resulting in improved pathogen control at day 7 p.i. Imaging flow cytometry revealed that A20-deficient Listeria-specific CD8+ T cells underwent increased apoptosis and necroptosis resulting in reduced numbers of memory CD8+ T cells. In contrast, the primary CD4+ T cell response was A20-independent. Upon secondary infection, the increase and function of pathogen-specific CD8+ T cells, as well as pathogen control were significantly impaired in CD4-Cre A20fl/fl mice. In vitro, apoptosis and necroptosis of Listeria-specific A20-deficient CD8+ T cells were strongly induced as demonstrated by increased caspase-3/7 activity, RIPK1/RIPK3 complex formation and more morphologically apoptotic and necroptotic CD8+ T cells. In vitro, A20 limited CD95L and TNF-induced caspase3/7 activation. In conclusion, T cell-specific A20 limited the expansion but reduced apoptosis and necroptosis of Listeria-specific CD8+ T cells, resulting in an impaired pathogen control in primary but improved clearance in secondary infection.

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Section: Discussionmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

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A20 Curtails Primary but Augments Secondary CD8+ T Cell Responses in Intracellular Bacterial Infection

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Nishanth

Buchbinder

et al. 2016

Sci Rep

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“…The specific deletion of A20 in enterocytes increased the susceptibility of mice to dextran sodium sulphate (DSS)-induced colitis and prevented recovery from DSS-induced inflammation[14], whereas the expression of A20 by dendritic cells protects mice from LPS-induced mortality and DSS-induced colitis[24,25]. Not limited to IBD, A20 was also identified to be associated with numerous autoimmune diseases[11,26].…”

Section: Discussionmentioning

confidence: 99%

A20 inhibits lipopolysaccharide-induced inflammation in enterocytes

Zheng¹,

Shi²,

Huang³

et al. 2016

WJGPT

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AIMTo examine the role of A20 in the regulation of intestinal epithelial cells (IECs) inflammation.METHODSUsing gene transfection, both stable overexpression and knockdown A20-expressed HT-29 cell lines were established. Accordingly, the cells were divided into the following groups: The control group, the A20 overexpression group, the A20 knockdown group and the respective controls. A20 was stimulated with lipopolysaccharide (LPS) in a dose- and time-dependent manner and was detected using western blotting and real-time polymerase chain reaction (PCR) analyses. Immunofluorescence and western blotting analyses were performed to investigate the role of A20 in the regulation of nuclear factor (NF)-κB activation and translocation into the nucleus. ELISA and real-time PCR were performed to examine A20 in regulating the release of the following inflammatory cytokines: Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-8.RESULTSThe expression of A20 in IECs was inducible. When intestinal epithelial cells were subjected to the stimulation of LPS, the expression of A20 was increased, and the expression of A20 was induced in a dose- and time-dependent manner. The expression of A20 was very low in HT-29 cells without LPS stimulation but rapidly increased and was maintained at a high level 2-4 h after stimulation with LPS. These levels gradually declined with a change in time-course, and the expression of A20 increased with increasing LPS stimulation. Western blotting and immunofluorescence revealed that overexpression of A20 can inhibit NF-κB activation and its translocation to the nucleus. The overexpression of A20 can reduce the levels of proinflammatory cytokines involved in the pathophysiology of inflammatory bowel disease. There was no significant difference in the expression of IL-8 mRNA in the control group, A20 overexpression group or A20 knockdown group without LPS stimulation (P > 0.05); however, while after 2 h, 4 h and 8 h stimulation with LPS, the expression of IL-8 in the A20 overexpression group was lower than the control group and the A20 knockdown group (P < 0.05 or P < 0.01). The expression of TNF-α was different at different time points after 8 h of LPS stimulation (F = 31.33, DF = 5, P < 0.001), and the expression of TNF-α increased as the LPS stimulation time increased. Upon LPS stimulation, lower levels of TNF-α were detected in the A20 overexpression cell lines (P < 0.05). There were no significant differences in the induction of IL-6 and IL-1β among the control group, A20 overexpression group and A20 knockdown group (P > 0.05).CONCLUSIONA20 plays an important role in limiting inflammation by inhibiting LPS-induced NF-κB responses in the gut luminal. A20 may be a potential therapeutic tool for inflammatory diseases.

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“…The results of TNFAIP3-deficient unfettered inflammation appears dependent upon cell type and other unknown factors: mice lacking TNFAIP3 specifically in lysozyme M expressing macrophages and granulocytes develop an RA phenotype, whereas mice conditionally deficient for TNFAIP3 in CD11c dendritic cells either develop SLE or manifest more of a spondyloarthritis phenotype, with enthesitis, axial disease, and gut pathology (independent studies performed at different institutions) (5–8). CD11c-specific TNFAIP3-deficient mice produce excess IL-2, IL-10, IL-12, IFN-γ, and TNF-α in response to LPS (9). …”

Section: Introductionmentioning

confidence: 99%

Genetic and Functional Associations with Decreased Anti-inflammatory Tumor Necrosis Factor Alpha Induced Protein 3 in Macrophages from Subjects with Axial Spondyloarthritis

Liu

et al. 2017

Front. Immunol.

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ObjectiveTumor necrosis factor alpha-induced protein 3 (TNFAIP3) is an anti-inflammatory protein implicated in multiple autoimmune and rheumatologic conditions. We hypothesized that lower levels of TNFAIP3 contributes to excessive cytokine production in response to inflammatory stimuli in axial spondyloarthritis (AxSpA). A further aim was to determine the immune signaling and genetic variation regulating TNFAIP3 expression in individual subjects.MethodsBlood-derived macrophages from 50 AxSpA subjects and 30 healthy controls were assessed for TNFAIP3 expression. Cell lysates were also analyzed for NF-κB, mitogen-activated protein (MAP) kinase and STAT3 phosphorylation, and supernatants for cytokine production. Coding and regulatory regions in the TNFAIP3 gene and other auto-inflammation-implicated genes were sequenced by next-generation sequencing and variants identified.ResultsMean TNFAIP3 was significantly lower in spondyloarthritis macrophages than controls (p = 0.0085). Spondyloarthritis subject macrophages correspondingly produced more TNF-α in response to lipopolysaccharide (LPS, p = 0.015). Subjects with the highest TNFAIP3 produced significantly less TNF-α in response to LPS (p = 0.0023). Within AxSpA subjects, those on TNF blockers or with shorter duration of disease expressed lower levels of TNFAIP3 (p = 0.0011 and 0.0030, respectively). TNFAIP3 expression correlated positively with phosphorylated IκBα, phosphorylated MAP kinases, and unstimulated phosphorylated STAT3, but negatively with LPS or TNF-α-stimulated fold induction of phosphorylated STAT3. Further, subjects with specific groups of variants within TNFAIP3 displayed differences in TNFAIP3 (p = 0.03–0.004). Nominal pQTL associations with genetic variants outside TNFAIP3 were identified.ConclusionOur results suggest that both immune functional and genetic variations contribute to the regulation of TNFAIP3 levels in individual subjects. Decreased expression of TNFAIP3 in AxSpA macrophages correlated with increased LPS-induced TNF-α, and thus, TNFAIP3 dysregulation may be a contributor to excessive inflammatory responses in spondyloarthritis subjects.

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A20 expression in dendritic cells protects mice from LPS‐induced mortality

Cited by 29 publications

References 40 publications

A20 Curtails Primary but Augments Secondary CD8+ T Cell Responses in Intracellular Bacterial Infection

A20 Curtails Primary but Augments Secondary CD8+ T Cell Responses in Intracellular Bacterial Infection

A20 inhibits lipopolysaccharide-induced inflammation in enterocytes

Genetic and Functional Associations with Decreased Anti-inflammatory Tumor Necrosis Factor Alpha Induced Protein 3 in Macrophages from Subjects with Axial Spondyloarthritis

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