Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions

Abstract Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer’s disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice heterozygous or homozygous for the Trem2 R47H AD risk variant. The prevailing phenotype of Trem2 R47H knock-in mice was decreased expression levels of Trem2 in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reduced Trem2 expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreased Trem2 expression under conditions of lipopolysaccharide (LPS) pro-inflammatory or IL-4 anti-inflammatory stimulation revealed the importance of Trem2 in driving a number of the genes up-regulated in the anti-inflammatory phenotype. RNA-seq analysis showed that IL-4 induced the expression of a program of genes including Arg1 and Ap1b1 in microglia, which showed an attenuated response to IL-4 when Trem2 expression was decreased. Genes showing a similar expression profile to Arg1 were enriched for STAT6 transcription factor recognition elements in their promoter, and Trem2 knockdown decreased levels of STAT6. LPS-induced pro-inflammatory stimulation suppressed Trem2 expression, thus preventing TREM2’s anti-inflammatory drive. Given that anti-inflammatory signaling is associated with tissue repair, understanding the signaling mechanisms downstream of Trem2 in coordinating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL-4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease.

Download Full-text

Trem2promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions

10.1101/449884 ◽

2018 ◽

Cited By ~ 1

Author(s):

Wenfei Liu ◽

Orjona Taso ◽

Rui Wang ◽

Sevinc Bayram ◽

Pablo Garcia-Reitboeck ◽

...

Keyword(s):

Transcription Factor ◽

Inflammatory Responses ◽

Association Studies ◽

Genome Wide Association Studies ◽

Similar Expression Profile ◽

Inflammatory Conditions ◽

Phenotype Comparison ◽

Inflammatory Phenotype ◽

Similar Phenotype ◽

Anti Inflammatory

AbstractGenome-wide association studies have reported that, amongst other microglial genes, variants inTREM2can profoundly increase the incidence of developing Alzheimer’s disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decreaseTrem2expression, and in parallel from knock-in mice heterozygous or homozygous for theTrem2R47H AD risk variant. The prevailing phenotype ofTrem2R47H knock-in mice was decreased expression levels ofTrem2in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reducedTrem2expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreasedTrem2expression under conditions of LPS pro-inflammatory or IL-4 anti-inflammatory stimulation revealed the importance ofTrem2in driving a number of the genes up-regulated in the anti-inflammatory phenotype. RNA-seq analysis showed that IL-4 induced the expression of a programme of genes includingArg1andAp1b1in microglia, which showed an attenuated response to IL-4 whenTrem2expression was decreased. Genes showing a similar expression profile toArg1were enriched for STAT6 transcription factor recognition elements in their promoter, andTrem2knockdown decreased levels of the transcription factor STAT6. LPS-induced pro-inflammatory stimulation suppressedTrem2expression, thus preventing TREM2’s anti-inflammatory drive. Given that anti-inflammatory signaling is associated with tissue repair, understanding the signaling mechanisms downstream ofTrem2in coordinating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL-4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease.Graphical abstract

Download Full-text

The CXCR6/CXCL16 axis links inflamm-aging to disease severity in COVID-19 patients

10.1101/2021.01.25.428125 ◽

2021 ◽

Author(s):

Daniel J. Payne ◽

Surita Dalal ◽

Richard Leach ◽

Richard Parker ◽

Stephen Griffin ◽

...

Keyword(s):

T Cells ◽

Inflammatory Responses ◽

Association Studies ◽

Significant Risk ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Inflammatory State ◽

Negative Controls ◽

Severe Lung Disease

AbstractAdvancing age and chronic health conditions, significant risk factors for severe COVID-19, are associated with a pro-inflammatory state, termed inflamm-aging. CXCR6+ T cells are known to traffic to the lung and have been reported to increase with age. The ligand of CXCR6, CXCL16, is constitutively expressed in the lung and upregulated during inflammatory responses and the CXCR6/CXCL16 axis is associated with severe lung disease and pneumonia. Genome-wide association studies have also recently identified 3p21.31, encompassing the CXCR6 gene, as a susceptibility locus for severe COVID-19. We assessed numbers T cells expressing the chemokine receptor CXCR6 and plasma levels of CXCL16, in control and COVID-19 patients. Results demonstrated that circulating CD8+CXCR6+ T cells were significantly elevated with advancing age, yet virtually absent in patients with severe COVID-19. Peripheral levels of CXCL16 were significantly upregulated in severe COVID-19 patients compared to either mild COVID-19 patients or SARS-CoV-2 negative controls. This study supports a significant role of the CXCR6/CXCL16 axis in the immunopathogenesis of severe COVID-19.

Download Full-text

Epigenetic Modifications and Therapy in Uveitis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.758240 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yanli Zou ◽

Jing Jing Li ◽

Wei Xue ◽

Xiangbin Kong ◽

Hucheng Duan ◽

...

Keyword(s):

Immune Responses ◽

Association Studies ◽

Intraocular Inflammation ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Epigenetic Mechanisms ◽

Inflammatory Conditions ◽

Genome Wide ◽

Different Types ◽

Vkh Disease

Uveitis is a sight-threatening intraocular inflammation, and the exact pathogenesis of uveitis is not yet clear. Recent studies, including multiple genome-wide association studies (GWASs), have identified genetic variations associated with the onset and progression of different types of uveitis, such as Vogt–Koyanagi–Harada (VKH) disease and Behcet’s disease (BD). However, epigenetic regulation has been shown to play key roles in the immunoregulation of uveitis, and epigenetic therapies are promising treatments for intraocular inflammation. In this review, we summarize recent advances in identifying epigenetic programs that cooperate with the physiology of intraocular immune responses and the pathology of intraocular inflammation. These attempts to understand the epigenetic mechanisms of uveitis may provide hope for the future development of epigenetic therapies for these devastating intraocular inflammatory conditions.

Download Full-text

Abstract 351: Mechano-sensitive Ppap2b Regulates Endothelial Responses to Athero-relevant Hemodynamic Forces

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.351 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Congqing Wu ◽

Cheng-Hsiang Kuo ◽

Chan Woo Kim ◽

Ru-Ting Huang ◽

Anna Birukova ◽

...

Keyword(s):

Carotid Artery ◽

Lysophosphatidic Acid ◽

Association Studies ◽

Integral Membrane Protein ◽

Genome Wide Association Studies ◽

Cell Alignment ◽

Disturbed Flow ◽

Inflammatory Phenotype ◽

Anti Inflammatory

Rationale: PhosPhatidic-Acid-Phosphatase-type-2B (PPAP2B), an integral membrane protein that inactivates lysophosphatidic acid, was implicated in coronary artery disease (CAD) by genome-wide association studies (GWAS). However, it is unclear whether GWAS-identified CAD genes including PPAP2B participate in mechanotransduction mechanisms by which vascular endothelia respond to local athero-relevant blood flows that contribute to the regional nature of atherosclerosis. Approach and Results: Reduced endothelial PPAP2B was detected in vivo in swine aortic arch exposed to chronic disturbed flow and in mouse carotid artery subjected to surgically-induced acute disturbed flow. In culture, elevated PPAP2B was measured in human aortic endothelial cells (HAEC) under athero-protective flow mimicking hemodynamics of human distal carotid artery when compared with athero-susceptible waveform representing flow in carotid sinus. Disturbed flow-induced miR-92a was identified as a direct posttranscriptional inhibitor of mechano-sensitive PPAP2B. PPAP2B suppression abrogated athero-protection of unidirectional flow, shown by elevation of inflammatory genes. Inhibition of lysophosphatidic acid receptor 1 restored the flow-dependent, anti-inflammatory phenotype in PPAP2B-deficient cells. Moreover, PPAP2B inhibition resulted in myosin-light-chain phosphorylation and intercellular gaps, which were abolished by inhibition of lysophosphatidic acid receptors 1 and 2. Expression-quantitative-trait-locus-mapping demonstrated PPAP2B CAD risk allele is not linked to PPAP2B expression in various human tissues but significantly associated with reduced PPAP2B in HAEC. Conclusions: Athero-relevant flows dynamically modulate endothelial PPAP2B expression through miR-92a regulation. Mechano-sensitive PPAP2B plays an indispensable role in mediating cell alignment, promoting anti-inflammatory phenotype and maintaining vascular integrity of endothelial monolayer under athero-protective flow.

Download Full-text

Metanalysis of genome-wide association studies for panic disorder suggest pathways and mechanisms of pathogenesis

10.1101/326017 ◽

2018 ◽

Author(s):

Rhayra Xavier do Carmo Silva ◽

Sueslene Prado Rocha ◽

Dainara Pereira dos Santos Souza ◽

Monica Gomes Lima-Maximino ◽

Caio Maximino

Keyword(s):

Panic Disorder ◽

Inflammatory Responses ◽

Drug Repositioning ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Mouse Strains ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genome Wide

AbstractPanic disorder (PD) is characterized by abrupt surges of intense fear and distress. There is evidence for a genetic component in this disorder. We ran a meta-analysis of genome-wide association studies of patients with PD, and found 25 single-nucleotide polymorphisms that were associated with the disorder. Causal gene prediction based on these polymorphisms uncovered 20 hits. Exploratory analyses suggested that these genes formed interactor networks, which was enriched in signaling pathways associated with immune and inflammatory responses, as well as growth factors and other developmental mediators. A subset of genes is enriched in limbic regions of the human brain and in microglia and myelinating oligodendrocytes of mice. While these genes were not associated with relevant neurobehavioral phenotypes in mutant mice, expression levels of several causal genes in the amygdala, prefrontal cortex, hippocampus, hypothalamus, and adrenal gland of recombinant mouse strains was associated with endophenotypes of fear conditioning. Drug repositioning prediction was unsuccessful, but this does not discard these genes and pathways as targets for investigational drugs. In general,ASB3,EIF2S2, RASGRF2, andTRMT2B(and its coded proteins) emerged as interesting targets for mechanistic research on PD. These exploratory findings point towards hypotheses of pathogenesis and neuropharmacology that need to be further investigated.

Download Full-text