Monocyte transcriptomes from patients with axial spondyloarthritis reveal dysregulated monocytopoiesis and a distinct inflammatory imprint

In patients with axial spondyloarthritis (axSpA), monocytes show a pre-activated phenotype. Gut inflammation is a trigger of monocyte activation and may also affect their development in the bone marrow (BM). As gut inflammation is commonly observed in axSpA patients, we performed a detailed analysis...

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Published in:	Arthritis research & therapy Vol. 23; no. 1; p. 246
Main Authors:	Karow, Fabian, Smiljanovic, Biljana, Grün, Joachim R, Poddubnyy, Denis, Proft, Fabian, Talpin, Alice, Hue, Christophe, Boland, Anne, Deleuze, Jean-François, Garchon, Henri-Jean, Ergenç, Ilkay, De Craemer, Ann-Sophie, Erben, Ulrike, Häupl, Thomas, Elewaut, Dirk, Breban, Maxime, Grützkau, Andreas, Syrbe, Uta
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 24-09-2021 BioMed Central BMC
Subjects:	Arthritis Biochemistry, Molecular Biology Biopsy Clustering Cytokines Diagnosis Gene expression Gene Expression Profiling Genetic aspects Genomics Gut translocation Health aspects Human health and pathology Humans Hypoxia Immunology Independent study Inflammation Innate immunity Life Sciences Monocytes Neutrophils Proteins Rhumatology and musculoskeletal system Serology Spondylarthritis - genetics Spondyloarthritis Spondyloarthropathies Statistical analysis Transcriptome Transcriptomes Germany France Transcriptomes Gut translocation Monocytes Spondyloarthritis
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Summary:	In patients with axial spondyloarthritis (axSpA), monocytes show a pre-activated phenotype. Gut inflammation is a trigger of monocyte activation and may also affect their development in the bone marrow (BM). As gut inflammation is commonly observed in axSpA patients, we performed a detailed analysis of monocyte transcriptomes of axSpA patients in two cohorts and searched for signs of activation and developmental adaptations as putative imprints of gut inflammation. Transcriptomes of blood CD14 monocytes of HLA-B27+ axSpA patients and healthy controls (HC) were generated by microarrays from cohort 1 and by RNA-sequencing from cohort 2. Differentially expressed genes from both analyses were subjected to gene set enrichment analysis (GSEA) and to co-expression analysis in reference transcriptomes from BM cells, blood cells and activated monocytes. As serological markers of translocation, 1,3 beta-glycan, intestinal fatty acid binding protein, and lipopolysaccharide binding protein (LBP) were determined by LAL and ELISA. Transcriptome analysis identified axSpA-specific monocyte signatures showing an imprint of LPS/cytokine-activated monocytes, late granulopoietic BM cells, blood neutrophils, and G-CSF-mobilized blood cells, which suggests LPS/TNF activation and more prominent BM adaptation promoting a neutrophil-like phenotype. GSEA mapped axSpA upregulated genes to inflammatory responses and TNFα signaling and downregulated probe-sets to metabolic pathways. Among translocation markers, LBP levels were significantly increased in axSpA patients vs. HC (p < 0.001). Stratified analysis by disease activity and stage identified an "active disease signature" (BASDAI ≥ 4) with an imprint of LPS/cytokine-activated monocytes and CD16 monocyte subsets. The "AS signature" (vs. non-radiographic axSpA) showed a reinforced neutrophil-like phenotype due to deprivation of dendritic cell transcripts. The neutrophil-like phenotype of axSpA monocytes points towards a biased monocytopoiesis from granulocyte-monocyte progenitors. This shift in monocytopoiesis and the LPS/cytokine imprint as well as the elevated LBP levels are indicators of systemic inflammation, which may result from bacterial translocation. The BM adaptation is most prominent in AS patients while disease activity appears to be linked to activation and trafficking of monocytes.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC8461951
ISSN:	1478-6362 1478-6354 1478-6362
DOI:	10.1186/s13075-021-02623-7