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.

中文翻译：

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中轴型脊柱关节炎患者的单核细胞转录组揭示了单核细胞生成失调和明显的炎症印记


在中轴型脊柱关节炎 (axSpA) 患者中，单核细胞表现出预激活表型。肠道炎症是单核细胞激活的触发因素，也可能影响其在骨髓 (BM) 中的发育。由于肠道炎症在 axSpA 患者中常见，因此我们对两个队列中 axSpA 患者的单核细胞转录组进行了详细分析，并寻找激活和发育适应的迹象作为肠道炎症的推定印记。 HLA-B27+ axSpA 患者和健康对照 (HC) 的血液 CD14+ 单核细胞的转录组是通过队列 1 的微阵列和队列 2 的 RNA 测序生成的。对两次分析中的差异表达基因进行基因集富集分析 (GSEA) 和对来自 BM 细胞、血细胞和活化单核细胞的参考转录组进行共表达分析。作为易位的血清学标志物，通过 LAL 和 ELISA 测定 1,3 β-聚糖、肠脂肪酸结合蛋白和脂多糖结合蛋白 (LBP)。转录组分析鉴定出 axSpA 特异性单核细胞特征，显示 LPS/细胞因子激活的单核细胞、晚期粒细胞生成的 BM 细胞、血液中性粒细胞和 G-CSF 动员的血细胞的印记，这表明 LPS/TNF 激活和更显着的 BM 适应促进中性粒细胞-样表型。 GSEA 将 axSpA 上调基因映射到炎症反应和 TNFα 信号传导，并将下调探针组映射到代谢途径。在易位标记物中，与 HC 患者相比，axSpA 患者的 LBP 水平显着升高 (p < 0.001)。按疾病活动度和阶段进行分层分析，确定了“活动性疾病特征”（BASDAI ≥ 4），带有 LPS/细胞因子激活的单核细胞和 CD16+ 单核细胞亚群的印记。 “AS 签名”（与 由于树突细胞转录物的缺失，非放射学 axSpA) 显示出增强的中性粒细胞样表型。 axSpA 单核细胞的中性粒细胞样表型指向粒细胞-单核细胞祖细胞的偏向单核细胞生成。单核细胞生成和 LPS/细胞因子印记的这种变化以及 LBP 水平升高是全身炎症的指标，这可能是由细菌易位引起的。 BM 适应在 AS 患者中最为突出，而疾病活动似乎与单核细胞的激活和运输有关。