Watanabe Haruki, Song Tengfei, Choi Jaewoo, Lee Moses, Choi Kwangmin, Kim Junhwan, Sherry Barbara, Diamond Betty, Zou Yong-Rui, Son Myoungsun
Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.
Department of Chemistry, Oregon State University, Corvallis, OR, United States.
Front Pharmacol. 2025 May 30;16:1588987. doi: 10.3389/fphar.2025.1588987. eCollection 2025.
Immune resilience is the capacity of the immune system to recover from sepsis-induced organ injury and reestablish host defense. While sepsis survivors are often viewed as immunocompromised, recent studies suggest that some may acquire adaptive immune traits that enhance resistance to secondary infections.
We employed a murine cecal ligation and puncture (CLP) model to study polymicrobial sepsis and subsequent immune responses. Listeria monocytogenes was used as a model intracellular pathogen to assess immune protection. We analyzed myeloid cell phenotypes using single-cell RNA sequencing and evaluated lipid metabolic changes through quantitative RT-PCR, immunohistochemistry, serum cytokine assays, and plasma lipidomics.
Sepsis-surviving mice showed enhanced resistance to Listeria infection. Single-cell RNA sequencing revealed transcriptional reprogramming in splenic CD11bLy6C myeloid cells, including downregulation of lipoprotein lipase and lipid efflux genes. CD11b myeloid cells exhibited increased lipid droplet accumulation, accompanied by elevated serum interferon-gamma (IFN-γ) levels. Plasma lipidomics identified systemic lipid remodeling, with increased phosphatidylserine and decreased phosphatidylinositol and phosphatidylglycerol levels.
Our findings suggest that sepsis survival induces lipid metabolic reprogramming in myeloid cells, contributing to enhanced immunity against intracellular pathogens. These insights reveal potential therapeutic targets within lipid metabolic pathways to improve host defense in sepsis survivors.
免疫恢复力是免疫系统从脓毒症诱导的器官损伤中恢复并重建宿主防御的能力。虽然脓毒症幸存者通常被视为免疫功能低下，但最近的研究表明，一些人可能获得适应性免疫特征，从而增强对继发性感染的抵抗力。
我们采用小鼠盲肠结扎和穿刺（CLP）模型来研究多微生物脓毒症及随后的免疫反应。以单核细胞增生李斯特菌作为细胞内病原体模型来评估免疫保护作用。我们使用单细胞RNA测序分析髓样细胞表型，并通过定量逆转录聚合酶链反应、免疫组织化学、血清细胞因子检测和血浆脂质组学评估脂质代谢变化。
脓毒症存活小鼠对李斯特菌感染表现出增强的抵抗力。单细胞RNA测序揭示了脾脏CD11bLy6C髓样细胞中的转录重编程，包括脂蛋白脂肪酶和脂质外流基因的下调。CD11b髓样细胞表现出脂质滴积累增加，同时血清干扰素-γ（IFN-γ）水平升高。血浆脂质组学确定了全身脂质重塑，磷脂酰丝氨酸增加，磷脂酰肌醇和磷脂酰甘油水平降低。
我们的研究结果表明，脓毒症存活会诱导髓样细胞中的脂质代谢重编程，有助于增强对细胞内病原体的免疫力。这些见解揭示了脂质代谢途径中的潜在治疗靶点，以改善脓毒症幸存者的宿主防御。
