Melanie Genoula
Xiaofei Li
Triantafyllos Chavakis
George Hajishengallis
| Melanie Genoula | Xiaofei Li | Triantafyllos Chavakis | George Hajishengallis |
Melanie Genoula1, Xiaofei Li1, Triantafyllos Chavakis2, George Hajishengallis1
1Department of Basic and Translational Sciences, University of Pennsylvania, School of Dental Medicine 2Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden
Introduction
Trained innate immunity (TII) is a form of memory that enhances the response of innate immune cells to secondary challenges independently of adaptive immunity. Systemic inflammatory stimuli can trigger TII in the bone marrow (BM) through long-lasting adaptations in hematopoietic stem and progenitor cells (HSPCs) resulting in myeloid bias and generation of myeloid cells with enhanced immune preparedness. Periodontitis can cause low-grade systemic inflammation, which may influence inflammatory comorbidities. Recently, we showed that ligature-induced periodontitis (LIP)-associated systemic inflammation in mice induced epigenetic rewiring of HSPCs leading to an enhancement of myeloid cells production with inflammatory disposition. To better understand the nature of the HSPC inflammatory adaptation, we performed an overall transcriptomic and epigenetic analysis of HSPCs during LIP.
Methods
Single cell ATAC-seq analysis of hematopoietic progenitors (LSKs) and granulocyte-macrophage progenitors (GMPs) was performed in LIP-subjected trained mice or untrained controls. Gene Ontology (GO) enrichment analysis of the differentially accessible regions (DARs) of LSKs and of the total cluster 5 GMPs-specific markers were performed using PANTHER. LSKs from 7-day-LIP-subjected and control mice were subjected to RNA-sequencing. Significantly differentially expressed genes (DEG) were subjected to GO enrichment analysis.
Results
GO enrichment analysis of the DARs of LSKs revealed terms such as ‘Positive regulation of MAPK cascade’. The GO enrichment analysis of the GMP cluster 5-specific markers, which was significantly enriched in trained mice, yielded terms such as ‘Positive regulation of stress-activated MAPK cascade’ and ‘Positive regulation of ERK1/2 cascade’, ‘Response to oxidative stress’, and ‘Lipid transport’. Subsequently, we analyzed the DEG from RNA-seq. GO enrichment analysis revealed that the terms ‘Regulation of lipid metabolic process’, ‘Glycosphingolipid metabolic process’, ‘Positive regulation of ROS metabolic process’, ‘Positive regulation of ERK1/2 cascade’ were overrepresented in the significantly up-regulated genes, whereas ‘Oxidative phosphorylation’, ‘Aerobic respiration’, ‘Cholesterol biosynthetic process’ were overrepresented in the significantly down-regulated genes.
Conclusion
Transcriptomic analysis in LSKs from LIP-subjected mice showed changes in lipid metabolism-related genes, which may lead to reduced cholesterol biosynthesis, enhanced free fatty acid uptake, beta oxidation and triacylglycerol accumulation, and an enhanced glycosphingolipid metabolism. These metabolic changes in a context of systemic inflammation could lead to epigenetic rewiring that underlies maladaptive TII on HSPCs. In conclusion, periodontitis appears to modulate the transcriptomic and metabolic activities of HSPCs toward an inflammatory memory phenotype.