Islam Md Monirul, Watanabe Eizo, Salma Umme, Ozaki Masayuki, Irahara Takayuki, Tanabe Subaru, Katsuki Ryusuke, Oishi Dai, Takeyama Naoshi
Department of Emergency and Critical Care Medicine, Aichi Medical University, Nagakute, Japan.
Department of Biochemistry and Biotechnology, University of Science and Technology Chittagong (USTC), Chattogram, Bangladesh.
Front Immunol. 2024 Dec 10;15:1493214. doi: 10.3389/fimmu.2024.1493214. eCollection 2024.
Sepsis is characterized by a concomitant early pro-inflammatory response by immune cells to an infection, and an opposing anti-inflammatory response that results in protracted immunosuppression. The primary pathological event in sepsis is widespread programmed cell death, or cellular self-sacrifice, of innate and adaptive immune cells, leading to profound immunological suppression. This severe immune dysfunction hampers effective primary pathogen clearance, thereby increasing the risk of secondary opportunistic infections, latent viral reactivation, multiple organ dysfunction, and elevated mortality. The types of cell death include apoptosis (type I programmed cell death), autophagy (type II programmed cell death), NETosis (a program for formation of neutrophil extracellular traps (NETs)) and other programmed cell deaths like pyroptosis, ferroptosis, necroptosis, each contributing to immunosuppression in distinct ways during the later phases of sepsis. Extensive apoptosis of lymphocytes, such as CD4+, CD8+ T cells, and B cells, is strongly associated with immunosuppression. Apoptosis of dendritic cells further compromises T and B cell survival and can induce T cell anergy or promote regulatory Treg cell proliferation. Moreover, delayed apoptosis and impaired neutrophil function contribute to nosocomial infections and immune dysfunction in sepsis. Interestingly, aberrant NETosis and the subsequent depletion of mature neutrophils also trigger immunosuppression, and neutrophil pyroptosis can positively regulate NETosis. The interaction between programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1) plays a key role in T cell modulation and neutrophil apoptosis in sepsis. The dendritic cell growth factor, Fms-like tyrosine kinase (FLTEL), increases DC numbers, enhances CD 28 expression, attenuates PD-L1, and improves survival in sepsis. Recently, immunoadjuvant therapies have attracted attention for their potential to restore host physiological immunity and homeostasis in patients with sepsis. This review focuses on several potential immunotherapeutic agents designed to bolster suppressed innate and adaptive immune responses in the management of sepsis.
脓毒症的特征是免疫细胞对感染同时产生早期促炎反应，以及导致持久免疫抑制的相反抗炎反应。脓毒症的主要病理事件是先天性和适应性免疫细胞广泛的程序性细胞死亡或细胞自我牺牲，导致严重的免疫抑制。这种严重的免疫功能障碍阻碍了有效的原发性病原体清除，从而增加了继发性机会性感染、潜伏病毒再激活、多器官功能障碍和死亡率升高的风险。细胞死亡类型包括凋亡（I型程序性细胞死亡）、自噬（II型程序性细胞死亡）、中性粒细胞胞外陷阱形成（NETosis）（一种形成中性粒细胞胞外陷阱（NETs）的程序）以及其他程序性细胞死亡，如焦亡、铁死亡、坏死性凋亡，它们在脓毒症后期以不同方式导致免疫抑制。淋巴细胞（如CD4 +、CD8 + T细胞和B细胞）的广泛凋亡与免疫抑制密切相关。树突状细胞的凋亡进一步损害T细胞和B细胞的存活，并可诱导T细胞无反应性或促进调节性Treg细胞增殖。此外，延迟凋亡和中性粒细胞功能受损导致脓毒症患者发生医院感染和免疫功能障碍。有趣的是，异常的NETosis和随后成熟中性粒细胞的消耗也会引发免疫抑制，并且中性粒细胞焦亡可正向调节NETosis。程序性细胞死亡1（PD - 1）或程序性细胞死亡1配体（PD - L1）之间的相互作用在脓毒症的T细胞调节和中性粒细胞凋亡中起关键作用。树突状细胞生长因子，Fms样酪氨酸激酶（FLTEL），可增加树突状细胞数量，增强CD 28表达，减弱PD - L1，并提高脓毒症患者的存活率。最近，免疫佐剂疗法因其在恢复脓毒症患者宿主生理免疫和内环境稳态方面的潜力而受到关注。本综述重点关注几种潜在的免疫治疗药物，这些药物旨在增强脓毒症治疗中被抑制的先天性和适应性免疫反应。
