The immune reaction against allogeneic necrotic cells is reduced in Annexin A5 knock out mice whose macrophages display an anti-inflammatory phenotype

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα, a nuclear receptor, plays a central role in the transcription of inflammatory and lipid metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the functional consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRa phosphorylation, bone marrow from LXRaWT and S196A mice was transplanted into Ldlr knock out mice, which were fed a high fat, high cholesterol diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68 cells from S196A mouse plaques revealed downregulation of proinflammatory genes and upregulation of mitochondrial genes characteristic of antiinflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue. This was associated with transcriptional reprograming of the adipose tissue macrophages and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα to an anti-inflammatory phenotype.

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Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype

European Respiratory Journal ◽

10.1183/13993003.00261-2020 ◽

2020 ◽

pp. 2000261

Author(s):

Mathias Declercq ◽

Pauline de Zeeuw ◽

Nadine Vasconcelos Conchinha ◽

Vincent Geldhof ◽

Anabela S. Ramalho ◽

...

Keyword(s):

Cystic Fibrosis ◽

Endothelial Cells ◽

Ex Vivo ◽

Leukocyte Adhesion ◽

Lung Damage ◽

Integrated Analysis ◽

Activation Markers ◽

Knock Out ◽

Inflammatory Phenotype ◽

Knock Out Mice

Cystic fibrosis (CF) is a life-threatening disorder characterised by decreased pulmonary mucociliary and pathogen clearance, and an exaggerated inflammatory response leading to progressive lung damage. CF is caused by bi-allelic pathogenic variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes a chloride channel. CFTR is expressed in endothelial cells (ECs) and EC dysfunction has been reported in CF patients, but a role for this ion channel in CF disease progression is poorly described.We used an unbiased RNA sequencing approach in complementary models of CFTR silencing and blockade (by the CFTR inhibitor CFTRinh-(172)) in human ECs to characterise the changes upon CFTR impairment. Key findings were further validated in vitro, in vivo in CFTR knock-out mice and ex vivo in CF patient-derived ECs.Both models of CFTR impairment revealed that EC proliferation, migration and autophagy were downregulated. Remarkably though, defective CFTR function led to EC activation and a persisting pro-inflammatory state of the endothelium with increased leukocyte adhesion. Further validation in CFTR knock-out mice revealed enhanced leukocyte extravasation in lung and liver parenchyma associated with increased levels of EC activation markers. In addition, CF patient-derived ECs displayed increased EC activation markers and leukocyte adhesion, which was partially rescued by using CFTR modulators VX770-VX809.Our integrated analysis thus suggests that ECs are no innocent bystanders in CF pathology, but rather may contribute to the exaggerated inflammatory phenotype, raising the question whether normalisation of vascular inflammation might be a novel therapeutic strategy to ameliorate the disease severity of CF.

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