Qin Huan, Wang Jiangang, Bai Luyuan, Ding Huiqin, Ding Hailing, Zhang Fengyi, Han Yantao
School of Basic Medicine, Qingdao University, Qingdao, China.
School of Basic Medicine, Qingdao University, Qingdao, China; Kanglitai Biopharmaceutical (Qingdao) Co. Ltd., Qingdao, China.
Int Immunopharmacol. 2025 Feb 6;147:113948. doi: 10.1016/j.intimp.2024.113948. Epub 2025 Jan 7.
This study investigates the therapeutic effects of recombinant human IL-10 (rhIL-10) administered via aerosol inhalation in acute lung injury (ALI), with a particular focus on neutrophils. It explores how rhIL-10, in the presence of platelets, modulates neutrophil polarization to ameliorate acute lung injury. Initially, the ALI model established in mice demonstrated that aerosol inhalation of rhIL-10 significantly mitigated the cytokine storm in the lungs, reduced pulmonary edema, and alleviated histopathological damage to lung tissue. Additionally, rhIL-10 administration was found to decrease neutrophil infiltration and platelet activation in the lungs of mice, inhibiting the formation of platelet-neutrophil aggregates (PNAs) and promoting the differentiation of neutrophils toward an anti-inflammatory phenotype in the presence of platelets. Subsequently, primary neutrophils and platelets were isolated from mouse bone marrow and blood to explore the underlying mechanisms. The results indicated that rhIL-10 promotes the expression of the signal transducer and activator of transcription 3 (STAT3) and the suppressor of cytokine signaling 3 (SOCS3) in neutrophils while inhibiting the activation of the nuclear factor kappa B (NF-κB) and the NF-κB inhibitor (IκB), which in turn enhances CD40 expression. This interaction facilitates the formation of PNAs and influences neutrophil phenotype differentiation. Furthermore, the application of the STAT3 phosphorylation inhibitor Stattic and CD40 antibody in vivo provided further validation of this potential mechanism. In conclusion, these results indicate that aerosol inhalation of rhIL-10 effectively ameliorates ALI. The underlying mechanism may involve the modulation of the neutrophil STAT/SOCS-IκB/NF-κB-CD40 signaling pathway, promoting interactions between neutrophils and platelets that facilitate the differentiation of neutrophils toward an anti-inflammatory phenotype.
本研究调查了通过雾化吸入给予重组人白细胞介素-10（rhIL-10）对急性肺损伤（ALI）的治疗效果，特别关注中性粒细胞。它探讨了在血小板存在的情况下，rhIL-10如何调节中性粒细胞极化以改善急性肺损伤。最初，在小鼠中建立的ALI模型表明，雾化吸入rhIL-10可显著减轻肺部的细胞因子风暴，减轻肺水肿，并减轻肺组织的组织病理学损伤。此外，发现给予rhIL-10可减少小鼠肺部的中性粒细胞浸润和血小板活化，抑制血小板-中性粒细胞聚集体（PNA）的形成，并在血小板存在的情况下促进中性粒细胞向抗炎表型分化。随后，从小鼠骨髓和血液中分离出原代中性粒细胞和血小板，以探究潜在机制。结果表明，rhIL-10促进中性粒细胞中信号转导和转录激活因子3（STAT3）和细胞因子信号抑制因子3（SOCS3）的表达，同时抑制核因子κB（NF-κB）和NF-κB抑制因子（IκB）的活化，这反过来又增强了CD40的表达。这种相互作用促进了PNA的形成并影响中性粒细胞表型分化。此外，体内应用STAT3磷酸化抑制剂Stattic和CD40抗体进一步验证了这一潜在机制。总之，这些结果表明雾化吸入rhIL-10可有效改善ALI。潜在机制可能涉及调节中性粒细胞STAT/SOCS-IκB/NF-κB-CD40信号通路，促进中性粒细胞与血小板之间的相互作用，从而促进中性粒细胞向抗炎表型分化。
