Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Critical Care Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
Int Immunopharmacol. 2023 Nov;124(Pt B):111017. doi: 10.1016/j.intimp.2023.111017. Epub 2023 Oct 7.
Macrophages infiltration is a crucial factor causing Sepsis-associated acute lung injury (ALI). Accumulating evidence suggests macrophages-alveolar epithelial cells communication is proven to be critical in ALI. However, little is known regarding how activated macrophages regulated sepsis-associated ALI. To explore the role of macrophages-alveolar epithelial cells communication in the ALI process, our data revealed that Lipopolysaccharides-induced macrophages-derived exosomes (L-Exo) induced sepsis-associated ALI and caused alveolar epithelial cells damage. Moreover, Guanylate-binding protein 2 (GBP2) was significantly upregulated in L-Exo, and NLRP3 inflammasomes was the direct target of GBP2. Further experimentation showed that GBP2 inhibition in vitro and in vivo reserves L-Exo effects, while GBP2 overexpression in vitro and in vivo promotes L-Exo effects. These results demonstrated that L-Exo contains excessive GBP2 and promotes inflammation through targeting NLRP3 inflammasomes, which induced alveolar epithelial cells dysfunction and pyroptosis. These findings demonstrate that L-Exo exerted a deleterious effect on ALI by regulating the GBP2/NLRP3 axis, which might provide new insight on ALI prevention and treatment.
巨噬细胞浸润是导致脓毒症相关性急性肺损伤（ALI）的关键因素。越来越多的证据表明，巨噬细胞-肺泡上皮细胞的通讯被证明在 ALI 中至关重要。然而，对于激活的巨噬细胞如何调节脓毒症相关性 ALI 知之甚少。为了探讨巨噬细胞-肺泡上皮细胞通讯在 ALI 过程中的作用，我们的数据显示，脂多糖诱导的巨噬细胞衍生的外泌体（L-Exo）诱导脓毒症相关性 ALI 并导致肺泡上皮细胞损伤。此外，GBP2 在 L-Exo 中显著上调，NLRP3 炎性小体是 GBP2 的直接靶标。进一步的实验表明，体外和体内抑制 GBP2 可保留 L-Exo 的作用，而体外和体内过表达 GBP2 可促进 L-Exo 的作用。这些结果表明，L-Exo 含有过量的 GBP2，并通过靶向 NLRP3 炎性小体促进炎症，从而导致肺泡上皮细胞功能障碍和细胞焦亡。这些发现表明，L-Exo 通过调节 GBP2/NLRP3 轴对 ALI 产生有害影响，这可能为 ALI 的预防和治疗提供新的见解。
