Department of Laboratory Medicine, Yuebei People's Hospital Affiliated to Shantou University Medical College, Shaoguan, China.
Laboratory for Diagnosis of Clinical Microbiology and Infection, Yuebei People's Hospital Affiliated to Shantou University Medical College, Shaoguan, China.
Front Immunol. 2024 Nov 14;15:1486322. doi: 10.3389/fimmu.2024.1486322. eCollection 2024.
Formyl peptide receptor 1 (FPR1) is a member of G protein-coupled receptor (GPCR) family that detects potentially danger signals characterized by the appearance of N-formylated peptides which originate from either bacteria or host mitochondria during organ injury, including sepsis. Mitochondrial-encoded NADH dehydrogenase 6 (MT-ND6) and Annexin A1 (ANXA1), as mitochondrial damage-associated molecular patterns (mtDAMPs) agonist and endogenous agonist of FPR1 respectively, interact with FPR1 regulating polymorphonuclear leukocytes (PMNs) function and inflammatory response during sepsis. However, there is no direct evidence of MT-ND6 or ANXA1 in the circulation of patients with sepsis and their potential role in clinical significance, including diagnosis and mortality prediction during sepsis.
A prospective cohort study was conducted in ICU within a large academic hospital. We measured serum MT-ND6 or ANXA1 in a cohort of patients with sepsis in ICU (n=180) and patients with non-sepsis in ICU (n=60) by Enzyme-linked immunosorbent assays (ELISA). The ROC curve and Kaplan Meier analysis was used to evaluate the diagnostic and prognostic ability of two biomarkers for patients with sepsis.
The concentration of MT-ND6 and ANXA1 were significantly elevated in the patients with sepsis, and the diagnostic values of MT-ND6 (0.789) for sepsis patients was second only to SOFA scores (AUC = 0.870). Higher serum concentrations of MT-ND6 (>1.41 ng/ml) and lower concentrations of ANXA1 (< 8.09 ng/mL) were closely related to the higher mortality in patients with sepsis, with the predictive values were 0.705 and 0.694, respectively. When patients with sepsis classified based on four pro-inflammation and two anti-inflammation cytokines, it was shown that combination of MT-ND6 and ANXA1 obviously improved the predictive values in the septic patients with mixed hyperinflammation or immunosuppression phenotypes.
Our findings provide valuable models testing patient risk prediction and strengthen the evidence for agonists of FPR1, MT-ND6 and ANXA1, as novel biomarker for patient selection for novel therapeutic agents to target mtDAMPs and regulator of GPCRs in sepsis.
甲酰肽受体 1（FPR1）是 G 蛋白偶联受体（GPCR）家族的成员，可检测到潜在的危险信号，其特征是在器官损伤过程中出现 N-甲酰肽，这些肽来源于细菌或宿主线粒体，包括脓毒症。线粒体编码的 NADH 脱氢酶 6（MT-ND6）和膜联蛋白 A1（ANXA1）分别作为线粒体损伤相关分子模式（mtDAMPs）激动剂和 FPR1 的内源性激动剂，与 FPR1 相互作用，调节脓毒症期间多形核白细胞（PMN）的功能和炎症反应。然而，脓毒症患者循环中没有直接证据表明存在 MT-ND6 或 ANXA1，其在临床意义（包括脓毒症期间的诊断和死亡率预测）中的潜在作用仍不清楚。
本研究采用前瞻性队列研究，在一家大型学术医院的 ICU 中进行。我们通过酶联免疫吸附试验（ELISA）检测了 ICU 中脓毒症患者（n=180）和非脓毒症患者（n=60）的血清 MT-ND6 或 ANXA1 浓度。ROC 曲线和 Kaplan-Meier 分析用于评估两种生物标志物对脓毒症患者的诊断和预后能力。
脓毒症患者的 MT-ND6 和 ANXA1 浓度明显升高，MT-ND6（0.789）对脓毒症患者的诊断价值仅次于 SOFA 评分（AUC=0.870）。较高的血清 MT-ND6 浓度（>1.41ng/ml）和较低的 ANXA1 浓度（<8.09ng/ml）与脓毒症患者的高死亡率密切相关，预测值分别为 0.705 和 0.694。当根据四种促炎和两种抗炎细胞因子对脓毒症患者进行分类时，结果表明 MT-ND6 和 ANXA1 的联合明显提高了混合高炎症或免疫抑制表型的脓毒症患者的预测值。
我们的研究结果提供了有价值的模型，用于检测患者的风险预测，并为 FPR1 的激动剂 MT-ND6 和 ANXA1 作为新型生物标志物提供了有力证据，可用于选择新型治疗药物以靶向脓毒症中的 mtDAMPs 和 GPCR 调节剂。
