Postoperative Innate Immune Dysregulation, Proteomic, and Monocyte Epigenomic Changes After Colorectal Surgery: A Substudy of a Randomized Controlled Trial.

Anesthesia & Analgesia Pub Date : 2024-10-25 DOI:10.1213/ane.0000000000007297

Kim I Albers-Warlé,Leonie S Helder,Laszlo A Groh,Fatih Polat,Ivo F Panhuizen,Marc M J Snoeck,Matthijs Kox,Lucas van Eijk,Leo A B Joosten,Mihai G Netea,Yutaka Negishi,Musa Mhlanga,Christiaan Keijzer,Gert-Jan Scheffer,Michiel C Warlé

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Abstract

BACKGROUND Colorectal surgery is associated with moderate-to-severe postoperative complications in over 25% of patients, predominantly infections. Monocyte epigenetic alterations leading to immune tolerance could explain postoperative increased susceptibility to infections. This research explores whether changes in monocyte DNA accessibility contribute to postoperative innate immune dysregulation. METHODS Damage-associated molecular patterns (DAMPs) and ex vivo cytokine production capacity were measured in a randomized controlled trial (n = 100) in colorectal surgery patients, with additional exploratory subgroup proteomic (proximity extension assay; Olink) and epigenomic analyses (Assay for Transposase-Accessible Chromatin [ATAC sequencing]). Monocytes of healthy volunteers were used to study the effect of high-mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70) on cytokine production capacity in vitro. RESULTS Plasma DAMPs were increased after surgery. HMGB1 showed a mean 235% increase from before- (preop) to the end of surgery (95% confidence interval [CI] [166 - 305], P < .0001) and 90% increase (95% CI [63-118], P = .0004) preop to postoperative day 1 (POD1). HSP70 increased by a mean 12% from preop to the end of surgery (95% CI [3-21], not significant) and 30% to POD1 (95% CI [18-41], P < .0001). Nuclear deoxyribonucleic acid (nDNA) increases by 66% (95% CI [40-92], P < .0001) at the end of surgery and 94% on POD1 (95% CI [60-127], P < .0001). Mitochondrial DNA (mtDNA) increases by 370% at the end of surgery (95% CI [225-515], P < .0001) and by 503% on POD1 (95% CI [332-673], P < .0001). In vitro incubation of monocytes with HSP70 decreased cytokine production capacity of tumor necrosis factor (TNF) by 46% (95% CI [29-64], P < .0001), IL-6 by 22% (95% CI [12-32], P = .0004) and IL-10 by 19% (95% CI [12-26], P = .0015). In vitro incubation with HMGB1 decreased cytokine production capacity of TNF by 34% (95% CI [3-65], P = .0003), interleukin 1β (IL-1β) by 24% (95% CI [16-32], P < .0001), and IL-10 by 40% (95% CI [21-58], P = .0009). Analysis of the inflammatory proteome alongside epigenetic shifts in monocytes indicated significant changes in gene accessibility, particularly in inflammatory markers such as CXCL8 (IL-8), IL-6, and interferon-gamma (IFN-γ). A significant enrichment of interferon regulatory factors (IRFs) was found in loci exhibiting decreased accessibility, whereas enrichment of activating protein-1 (AP-1) family motifs was found in loci with increased accessibility. CONCLUSIONS These findings illuminate the complex epigenetic modulation influencing monocytes' response to surgical stress, shedding light on potential biomarkers for immune dysregulation. Our results advocate for further research into the role of anesthesia in these molecular pathways and the development of personalized interventions to mitigate immune dysfunction after surgery.

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结直肠手术后先天性免疫失调、蛋白质组和单核细胞表观基因组的变化：一项随机对照试验的子研究。

背景：超过 25% 的患者在直肠手术后会出现中度至重度并发症，主要是感染。导致免疫耐受的单核细胞表观遗传学改变可解释术后感染易感性增加的原因。方法在一项随机对照试验（n = 100）中对结直肠手术患者的损伤相关分子模式（DAMPs）和体内外细胞因子生产能力进行了测量，并进行了额外的探索性亚组蛋白质组（接近延伸测定；Olink）和表观基因组分析（转座酶可及染色质测定[ATAC测序]）。健康志愿者的单核细胞被用来研究高迁移率组盒 1 (HMGB1) 和热休克蛋白 70 (HSP70) 对体外细胞因子生产能力的影响。HMGB1 从术前（preop）到手术结束平均增加了 235%（95% 置信区间 [CI] [166-305]，P < .0001），术前到术后第 1 天（POD1）平均增加了 90%（95% CI [63-118]，P = .0004）。HSP70 从术前到手术结束平均增加 12%（95% CI [3-21]，无显著性意义），到术后第 1 天平均增加 30%（95% CI [18-41]，P < .0001）。核脱氧核糖核酸（nDNA）在手术结束时增加了 66%（95% CI [40-92]，P < .0001），在 POD1 时增加了 94%（95% CI [60-127]，P < .0001）。线粒体 DNA（mtDNA）在手术结束时增加 370%（95% CI [225-515]，P < .0001），在 POD1 时增加 503%（95% CI [332-673]，P < .0001）。用 HSP70 对单核细胞进行体外培养可使肿瘤坏死因子 (TNF) 的细胞因子生成能力降低 46%（95% CI [29-64]，P < .0001），IL-6 降低 22%（95% CI [12-32]，P = .0004），IL-10 降低 19%（95% CI [12-26]，P = .0015）。体外孵育 HMGB1 可使 TNF 的细胞因子生产能力降低 34%（95% CI [3-65]，P = .0003），白细胞介素 1β (IL-1β) 降低 24%（95% CI [16-32]，P < .0001），IL-10 降低 40%（95% CI [21-58]，P = .0009）。在分析单核细胞表观遗传变化的同时分析炎症蛋白质组，结果表明基因的可及性发生了显著变化，尤其是炎症标志物，如 CXCL8 (IL-8)、IL-6 和干扰素-γ (IFN-γ)。这些发现阐明了影响单核细胞对手术应激反应的复杂表观遗传调控，并揭示了免疫失调的潜在生物标志物。我们的研究结果主张进一步研究麻醉在这些分子通路中的作用，并开发个性化干预措施以减轻术后免疫功能紊乱。

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Anesthesia & Analgesia

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