Akama Yuichi, Chen Jespar, Jha Alok, Lee Yongchan, Ma Gaifeng, Li Jingsong, Murao Atsushi, Wang Ping, Aziz Monowar
Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States.
Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States.
Front Immunol. 2025 Jun 11;16:1597887. doi: 10.3389/fimmu.2025.1597887. eCollection 2025.
Sepsis is a dysregulated immune response to infection. B-1a cells play a crucial role in maintaining immuno-physiologic homeostasis. Sialic acid-binding immunoglobulin-like lectin G (Siglec-G) regulates B-1a cell's behavior and function. Trogocytosis is the process by which one cell acquires portions of another cell's plasma membrane and cytoplasm through direct contact. During sepsis, neutrophils accumulate in the lungs and serosal cavities, while B-1a cells decrease. We hypothesized that neutrophil-mediated trogocytosis causes B-1a cell depletion in sepsis, and that targeting this process could preserve B-1a cells and attenuate sepsis-induced acute lung injury (ALI). Sepsis was induced in mice by cecal ligation and puncture (CLP). Twenty hours after CLP, B-1a cells (CD19B220CD23CD5) in the pleural and peritoneal cavities were quantified, and neutrophil engulfment of B-1a cells as well as trogocytosis were assessed. We also examine the interaction between Siglec-G and the "don't-eat-me" signal receptor, CD47. Our data showed that B-1a cell numbers and frequencies in the pleural and peritoneal cavities were significantly decreased in sepsis. Neutrophils co-cultured with B-1a cells significantly increased B-1a cell internalization via trogocytosis. We observed a strong binding interaction between Siglec-G and CD47, which facilitates neutrophil-mediated trogocytosis by compromising CD47 function. We discovered a novel 11-aa therapeutic peptide, named Compound 11 (C11), derived from the CD47 region interacting with Siglec-G. C11 effectively preserved B-1a cell populations, significantly reduced pro-inflammatory cytokine levels, alleviated ALI, and improved survival in sepsis. Our findings highlight the Siglec-G/CD47 axis on B-1a cells as a key regulator of neutrophil-mediated B-1a cell depletion. Targeting this pathway with C11 represents a promising therapeutic strategy to mitigate immune dysregulation and improve sepsis outcomes.
脓毒症是对感染的免疫反应失调。B-1a细胞在维持免疫生理稳态中起关键作用。唾液酸结合免疫球蛋白样凝集素G（Siglec-G）调节B-1a细胞的行为和功能。噬细胞作用是一个细胞通过直接接触获取另一个细胞质膜和细胞质部分的过程。在脓毒症期间，中性粒细胞在肺和浆膜腔中积聚，而B-1a细胞减少。我们假设中性粒细胞介导的噬细胞作用导致脓毒症中B-1a细胞耗竭，并且靶向这一过程可以保护B-1a细胞并减轻脓毒症诱导的急性肺损伤（ALI）。通过盲肠结扎和穿刺（CLP）在小鼠中诱导脓毒症。CLP后20小时，对胸膜腔和腹膜腔中的B-1a细胞（CD19+B220+CD23-CD5+）进行定量，并评估中性粒细胞对B-1a细胞的吞噬以及噬细胞作用。我们还研究了Siglec-G与“别吃我”信号受体CD47之间的相互作用。我们的数据显示，脓毒症时胸膜腔和腹膜腔中B-1a细胞的数量和频率显著降低。与B-1a细胞共培养的中性粒细胞通过噬细胞作用显著增加了B-1a细胞的内化。我们观察到Siglec-G与CD47之间有强烈的结合相互作用，这通过损害CD47功能促进了中性粒细胞介导的噬细胞作用。我们发现了一种新的11个氨基酸的治疗性肽，命名为化合物11（C11），它源自与Siglec-G相互作用的CD47区域。C11有效地保护了B-1a细胞群体，显著降低促炎细胞因子水平，减轻ALI，并提高脓毒症小鼠的存活率。我们的研究结果突出了B-1a细胞上的Siglec-G/CD47轴是中性粒细胞介导的B-1a细胞耗竭的关键调节因子。用C11靶向这一途径代表了一种有前景的治疗策略，可减轻免疫失调并改善脓毒症的预后。
