Ahmed Alaswad (1,2), Georgiana Cabău (4), Tania O. Crişan (3,4), Liang Zhou (1,2), Martijn Zoodsma (1,2), HINT Consortium (4), Mihai G Netea (3,5), Cheng-Jian Xu (1,2) Yang Li (1,2), Leo A. B. Joosten (3,4)
Affiliation(s):
1. Department of Computational Biology for Individualized Infection Medicine, Centre for Individualized Infection Medicine, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
2. TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
3. Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
4. Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania4.
5. Department of Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
Background/objectives: Gout, a prevalent inflammatory arthritis, is associated with urate crystal deposition and immune cell activation. However, the precise contribution of immune cells, specifically CD14 monocytes, in initiating this inflammatory disease remains a pivotal and evolving inquiry. Using single-cell transcriptome of patients and controls from multiple cohorts, this study utilized an integrative approach to robustly characterize the molecular and cellular landscapes of CD14 monocytes in gout. Furthermore, the study examined the intersection of the identified gout transcriptome with in vitro monosodium urate (MSU)-induced genes or with genes prioritized for a potential role in inflammation by the most recent gout GWAS, shedding light on different angles to deepen the understanding of CD14 monocyte's role in this disease.
Status: The project is currently in the manuscript drafting stage.
Methodology: In this cross-sectional case-control study, peripheral blood mononuclear cells (PBMCs) were collected from 8 patients with gout and 6 healthy donors (discovery group). The collected PBMCs were subjected to scRNA sequencing to characterize their transcriptome profile. We used different supporting online data to replicate, validate, or explain the findings from the discovery group.
Findings: At the molecular level, we previewed how HIF1A and hypoxia-related pathways are vastly involved in regulating IL-1β production from CD14 monocytes in gout. We also recorded the significant downregulation of CLEC12A expression along all CD14 monocytes subclusters. At the cellular level, we identified the S100Ahigh CD14 monocyte subcluster, which we found responsible for NLRP3 and CLEC7 inflammasome pathways as well as prostaglandin secretion from CD14 monocytes in gout. Furthermore, examining the in vitro MSU-induced differentially expressed genes (DEGs) showed high enrichment and consistency with the S100Ahigh CD14 monocyte gout-enriched DEGs, confirming how these two arms jointly build up inflammation in gout. Finally, GWAS-prioritized genes highlighted the importance of fatty acid metabolism, ending with significant enrichment of the prostaglandin excretion pathway from S100Ahigh CD14 monocytes in gout, a finding which we can replicate as well using the public data.
Significance: This study advanced the understanding of the role of CD14 monocytes in gout through a comprehensive molecular profile. The identified genes and cell subcluster markers offer promising therapeutic targets in various inflammatory or regulatory pathways, emphasizing precision medicine's potential in gout management.