Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
Front Immunol. 2019 Apr 15;10:791. doi: 10.3389/fimmu.2019.00791. eCollection 2019.
Most DAMPs in inflammatory diseases are TLR2- and TLR4-ligands and according to the current concept, repeated stimuli would result in tolerance. Aims of the study were to verify this assumption, to investigate whether epigenetic effectors are involved and to explore the situation in rheumatoid arthritis (RA). A trained immunity (TI) and tolerance protocol was established using peripheral blood monocytes from healthy donors, β-glucan and lipopolysaccharide (LPS). The training or tolerance capacities of RA-relevant DAMPs were tested. β-Glucan-, oS100A4-, HMBG1-, and HSP90-pretreated monocytes showed increased IL-6 responses to LPS re-stimulation. β-Glucan, oS100A and tenascin C induced training of monocytes to release more TNFα. In comparison to β-glucan, most DAMPs tested induced less TI, with exception of oS100A4. Monocytes exposed to oS100A4 showed increased IL-1β, IL-6, and TNFα in response to LPS, in spite that both stimulate TLR4. RNASEq upon β-glucan or oS100A4 revealed similar changes in chemokines/cytokines and epigenetic effectors; 17 epigenetic effectors correlated with chemokine/cytokine gene expression; PRDM8 was associated with more chemokine and cytokine transcripts. Knockdown of PRDM8 abolished TI induced by oS100A4. In RA, plasma S100A4 correlated with increased CSF2, and increased PRDM8 transcription in RA monocytes was associated with increased plasma CCL5 and IL-6, as well as therapy-resistance. Bypass of tolerance by DAMPs might be a phenomenon as important as TI, since it could explain how chronic inflammation can be maintained in spite of an environment with multiple TLR2/TLR4-ligands. In RA monocytes, a PRDM8-dependent TI mechanism could be responsible for sustained chemokine/cytokines levels.
在炎症性疾病中，大多数 DAMPs 是 TLR2 和 TLR4 的配体，根据当前的概念，重复的刺激会导致耐受。本研究的目的是验证这一假设，研究是否涉及表观遗传效应物，并探讨类风湿关节炎 (RA) 的情况。 使用来自健康供体的外周血单核细胞、β-葡聚糖和脂多糖 (LPS) 建立了训练免疫 (TI) 和耐受方案。测试了与 RA 相关 DAMPs 的训练或耐受能力。 β-葡聚糖、oS100A4、HMBG1 和 HSP90 预处理的单核细胞对 LPS 再刺激显示出更高的 IL-6 反应。β-葡聚糖、oS100A 和 tenascin C 诱导单核细胞释放更多 TNFα 进行训练。与 β-葡聚糖相比，大多数测试的 DAMPs 引起的 TI 较少，但 oS100A4 除外。暴露于 oS100A4 的单核细胞对 LPS 的反应显示出更高的 IL-1β、IL-6 和 TNFα，尽管两者都刺激 TLR4。β-葡聚糖或 oS100A4 后进行的 RNASEq 显示趋化因子/细胞因子和表观遗传效应物的相似变化；17 个表观遗传效应物与趋化因子/细胞因子基因表达相关；PRDM8 与更多的趋化因子和细胞因子转录本相关。PRDM8 的敲低消除了 oS100A4 诱导的 TI。在 RA 中，血浆 S100A4 与 CSF2 增加相关，并且 RA 单核细胞中 PRDM8 转录的增加与血浆 CCL5 和 IL-6 的增加以及治疗耐药性相关。 DAMPs 绕过耐受可能是与 TI 一样重要的现象，因为它可以解释为什么尽管存在多个 TLR2/TLR4 配体的环境，慢性炎症仍能持续存在。在 RA 单核细胞中，PRDM8 依赖性 TI 机制可能负责维持持续的趋化因子/细胞因子水平。
