Ramón-Luing Lucero A, Martínez-Gómez Laura Edith, Martinez-Armenta Carlos, Martínez-Nava Gabriela Angélica, Medina-Quero Karen, Pérez-Rubio Gloria, Falfán-Valencia Ramcés, Buendia-Roldan Ivette, Flores-Gonzalez Julio, Ocaña-Guzmán Ranferi, Selman Moisés, López-Reyes Alberto, Chavez-Galan Leslie
Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico.
Laboratorio de Gerociencias, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14080, Mexico.
Int J Mol Sci. 2025 Jan 28;26(3):1139. doi: 10.3390/ijms26031139.
TNF and IFN-γ are key proinflammatory cytokines implicated in the pathophysiology of COVID-19. Toll-like receptor (TLR)7 and TLR8 are known to recognize SARS-CoV-2 and induce TNF and IFN-γ production. However, it is unclear whether TNF and IFN-γ levels are altered through TLR-dependent pathways and whether these pathways mediate disease severity during COVID-19. This study aimed to investigate the association between TNF/IFN-γ levels and immune cell activation to understand their role in disease severity better. We enrolled 150 COVID-19 patients, who were classified by their systemic TNF and IFN-γ levels (high (H) or normal-low (N-L)) as TNFIFNγ, TNFIFNγ, TNFIFNγ, and TNFIFNγ. Compared to patients with TNFIFNγ, patients with TNFIFNγ had high systemic levels of pro- and anti-inflammatory cytokines and cytotoxic molecules, and their T cells and monocytes expressed TNF receptor 1 (TNFR1). Patients with TNFIFNγ presented the SNP rs3853839 to TLR7 and increased levels of MYD88, NFκB, and IRF7 (TLR signaling), FADD, and TRADD (TNFR1 signaling). Moreover, critical patients were observed in the four COVID-19 groups, but patients with TNFIFNγ or TNFIFNγ most required invasive mechanical ventilation. We concluded that increased TNF/IFN-γ levels are associated with hyperactive immune cells, whereas normal/low levels are associated with hypoactivity, suggesting a model to explain that the pathophysiology of critical COVID-19 may be mediated through different pathways depending on TNF and IFN-γ levels. These findings highlight the potential for exploring the modulation of TNF and IFN-γ as a therapeutic strategy in severe COVID-19.
肿瘤坏死因子（TNF）和干扰素-γ（IFN-γ）是参与新型冠状病毒肺炎（COVID-19）病理生理学过程的关键促炎细胞因子。已知Toll样受体（TLR）7和TLR8可识别严重急性呼吸综合征冠状病毒2（SARS-CoV-2）并诱导TNF和IFN-γ产生。然而，尚不清楚TNF和IFN-γ水平是否通过TLR依赖途径改变，以及这些途径是否在COVID-19期间介导疾病严重程度。本研究旨在探讨TNF/IFN-γ水平与免疫细胞活化之间的关联，以更好地了解它们在疾病严重程度中的作用。我们招募了150例COVID-19患者，根据其全身TNF和IFN-γ水平（高（H）或正常低（N-L））分为TNFIFNγ、TNFIFNγ、TNFIFNγ和TNFIFNγ组。与TNFIFNγ患者相比，TNFIFNγ患者的促炎和抗炎细胞因子及细胞毒性分子全身水平较高，且其T细胞和单核细胞表达肿瘤坏死因子受体1（TNFR1）。TNFIFNγ患者存在TLR7的单核苷酸多态性rs3853839，且髓样分化因子88（MYD88）、核因子κB（NFκB）和干扰素调节因子7（IRF7）（TLR信号传导）、Fas相关死亡结构域蛋白（FADD）和TNFR相关死亡结构域蛋白（TRADD）（TNFR1信号传导）水平升高。此外，在四个COVID-19组中均观察到重症患者，但TNFIFNγ或TNFIFNγ组患者最需要有创机械通气。我们得出结论，TNF/IFN-γ水平升高与免疫细胞过度活化相关，而正常/低水平与活性不足相关，这提示了一个模型来解释重症COVID-19的病理生理学可能通过依赖于TNF和IFN-γ水平的不同途径介导。这些发现突出了探索调节TNF和IFN-γ作为重症COVID-19治疗策略的潜力。
