Journal Article Epublish 3 citations
PubMed: 40521191 DOI: 10.7150/thno.109513
KLK8/HGF/Met signaling pathway mediates diabetes-associated hippocampal neuroinflammation in male mice.
Theranostics 15(13):6290-6312
Authors: Dan-Hong Xu, Xiao-Yong Zhang, Shi-Yu Liu, Juan Wei, Jun-Hui Zhan, Jian-Kui Du, Yu-Jian Liu, Xiao-Yan Zhu
Affiliations
- Department of Physiology, Naval Medical University, Shanghai, 200433, China.
- School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, 200438, China.
- School of Sports and Health, Nanjing Sport Institute, Nanjing, 210014, China.
Abstract
Rationale: Neuroinflammation plays a critical role in the pathogenesis of diabetes-associated depression. Tissue kallikrein-related peptidase 8 (KLK8), a secreted serine protease, has been implicated in the pathogenesis of depression- and anxiety-related behaviors across various etiologies, however the underlying mechanisms remain largely unexplored. This study elucidates a novel mechanism by which KLK8 upregulation contributes to diabetes-induced microglial activation and neuroinflammation in the hippocampus through modulating the hepatocyte growth factor (HGF)/Met signaling pathway. Methods and Results: Streptozotocin (STZ)-induced diabetic mice exhibited increased KLK8 expression in the hippocampus, an effect that was mitigated in KLK8-deficient or aerobic running-exercised mice. KLK8 deficiency significantly reduced depression-like behaviors, microglial activation, and neuroinflammation in diabetic mice. In BV2 mouse microglial cells, adenovirus-mediated overexpression of KLK8 (Ad-KLK8) was sufficient to induce microglial activation. Co-immunoprecipitation (Co-IP) coupled with mass spectrometry revealed that CD44 might interact with KLK8. KLK8 overexpression decreased CD44 levels in microglial cells. However, the CD44 activator Angstrom6 further exacerbated KLK8-induced microglial activation. Conversely, transcriptional profiling of KLK8-overexpressing microglial cells and subsequent validation demonstrated that the Met/Src/Btk/NF-κB signaling pathway played a central role in mediating the stimulatory effects of KLK8 on microglial activation in both Ad-KLK8-treated BV2 cells and human microglial cell line HMC3 cells stably transfected with KLK8 lentivirus (Lv-KLK8). The Met receptor is activated upon binding to its ligand HGF, which exists as an inactive precursor (pro-HGF). Our findings showed that KLK8 cleaved pro-HGF, promoting HGF release and subsequently activating the Met/Src/Btk/NF-κB signaling pathway in microglial cells. High glucose conditions increased KLK8 expression and enhanced HGF release, thereby stimulating the Met/Src/Btk/NF-κB signaling pathway and microglial activation in a KLK8-dependent manner. Systemic administration of a Met inhibitor inactivated the Met/Src/Btk/NF-κB pathway, reducing depression-like behaviors, microglial activation, and neuroinflammation in STZ-induced diabetic mice. Both Met inhibitor and KLK8 deficiency enhanced hippocampal neuroplasticity in STZ-induced diabetic mice. Finally, we demonstrated that running exercise reversed KLK8 upregulation and inactivated Met/Src/Btk/NF-κB signaling pathways, thereby attenuating neuroinflammation, improving neuroplasticity, and alleviating depression-like behaviors in STZ-induced diabetic mice. Conclusions: This study provides evidence that the KLK8/HGF/Met signaling pathway mediates diabetes-associated hippocampal neuroinflammation and depression-like behaviors, highlighting the therapeutic potential of targeting this pathway in diabetes-associated depression.
MeSH
Diabetes Mellitus, Depression, Exercise, Hippocampus, Microglia, Cells, Up-Regulation, Nanomedicine, Neuronal Plasticity, Running, Hepatocyte Growth Factor, Peptide Hydrolases