Session Type: Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Neutrophils are important mediators of immune defense as well as key protagonists in immune-mediated disease. How these cells adapt differently to sterile and septic inflammatory conditions may offer opportunities to target neutrophils without disarming immune defense.
Methods: Here, we applied an in-depth, cross-species and cross-condition analysis of publicly available RNA sequencing data from 286 neutrophil populations from 26 different datasets. Condition-variance versus species-variance was calculated on a per-gene basis. Similarities and differences between conditions were examined by KEGG pathways, gene ontology (GO), and principal component analysis (PCA). The regulatory activity of transcription factors was predicted using ENCODE and ChEA3 libraries.
Results: 87% of human genes could be assigned one-to-one murine orthologs with high confidence according to ENSEMBL version 100. The overall transcriptional landscape of healthy human and murine neutrophils exhibited strong correlation (Pearson’s R = 0.66; P < 2.2 × 10−16). By PCA, human blood neutrophils resembled murine blood neutrophils more than neutrophils from murine bone marrow, spleen and liver.
Within orthologous genes that exhibited a high dynamic range, 48% varied more between species than between experimental conditions. These genes were enriched for GO terms including cell-cell adhesion and metabolism. By contrast, 52% displayed higher variance between experimental conditions, reflecting conserved transcriptional responses in human and murine neutrophils. Condition-variant genes were associated with immune function and degranulation. A query of the GWAS catalog for SNPs associated with these genes identified association with immune-mediated conditions including allergy, psoriasis, rheumatoid arthritis and systemic lupus erythematosus.
We then compared different disease states. Neutrophils from aortic aneurysms, PAPA syndrome, influenza vaccination and CD200R-knockout mice exhibited few differences from healthy controls. By contrast, systemic juvenile idiopathic arthritis blood neutrophils differed from healthy human blood neutrophils by more than 300 genes. We identified a 151-gene transcriptomic inflammatory response program conserved across a broad range of conditions and between humans and mice, including elevation of NFKBIA, TNFAIP3, SOCS3, IL1B and CCL2. Transcription factor enrichment analysis implicated NFKB1, RELA, STAT1 and JUN as key drivers (P < 1 ×10−6), consistent with strong enrichment for the GO terms associated with NFkB activation and cytokine response.
Conclusion: Through a comparison of neutrophils across species and conditions, we identified substantially conserved transcriptomic responses between human and murine neutrophils. We define a conserved neutrophil inflammatory response program preserved across species and conditions. These findings provide new insight into the selection of potential targets for therapeutic manipulation of the contribution of neutrophils to sterile inflammatory diseases.
To cite this abstract in AMA style:Radtke F, Huang F, Nigrovic P, Grieshaber-Bouyer R. A Cross-Species Map of Neutrophil Inflammatory Responses [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/a-cross-species-map-of-neutrophil-inflammatory-responses/. Accessed December 5, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-cross-species-map-of-neutrophil-inflammatory-responses/