GPNMB modulates neutrophil extracellular trap formation: therapeutic implications for ischemic stroke
Ningning Zong1, Jian Chen1, Yang Geng1
1Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China.
Abstract:
Microglia are key immune-competent cells responding immediately to manipulate post-stroke neuroinflammation to shape the prognosis of stroke. GPNMB was reported to be upregulated after ischemic stroke and might influence the outcome. However, its detailed biological function and mechanism remain elusive. Here, we found that GPNMB was remarkably elevated in the ischemic brain and mainly distributed in microglia. Combining GPNMB knockout mice and recombinant GPNMB protein, we found that GPNMB could alleviate ischemic brain injury. Recombinant GPNMB (rGPNMB) administration could reduce neutrophil extracellular traps (NETs) formation, while knockout of GPNMB promoted NET formation in ischemic stroke. In addition, we found that CD44 functioned importantly in mediating the role of GPNMB inhibiting NET formation and alleviating ischemic brain injury. Depletion of neutrophils or inhibition of NET formation with DNase I could reduce the neuroprotective impact of GPNMB. Mechanistically, GPNMB might inhibit NET formation partly via modulating the Rac-ROS pathway after binding to the CD44 receptor. Finally, our data indicated that delayed rGPNMB administration retained neuroprotective impact in ischemic stroke. Our study revealed the importance of GPNMB in modulating NET formation and suggested a potential target for manipulating post-stroke neutrophil-associated neuroinflammation.
Insights
Glycoprotein non-metastatic melanoma protein B (GPNMB) alleviates ischemic stroke injury by reducing neutrophil extracellular traps (NETs). This discovery highlights GPNMB as a potential therapeutic target for stroke neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Microglia are crucial for post-stroke neuroinflammation and recovery.
- Glycoprotein non-metastatic melanoma protein B (GPNMB) is upregulated after ischemic stroke, but its function is unclear.
Purpose of the Study:
- To investigate the role of GPNMB in ischemic stroke and its underlying mechanisms.
- To explore GPNMB's potential as a therapeutic target for stroke.
Main Methods:
- Utilized GPNMB knockout mice and recombinant GPNMB protein administration.
- Assessed neutrophil extracellular traps (NETs) formation, Rac-ROS pathway, and CD44 receptor interaction.
- Investigated the effects of neutrophil depletion and DNase I inhibition.
Main Results:
- GPNMB expression is elevated in ischemic brain regions, primarily in microglia.
- GPNMB administration reduced ischemic brain injury and NET formation.
- GPNMB's protective effects involve CD44 and the Rac-ROS pathway, and are dependent on neutrophils and NETs.
- Delayed GPNMB administration also showed neuroprotective benefits.
Conclusions:
- GPNMB plays a significant neuroprotective role in ischemic stroke by inhibiting NET formation.
- GPNMB, via CD44 and the Rac-ROS pathway, modulates neuroinflammation.
- GPNMB represents a promising therapeutic target for managing post-stroke neuroinflammation and improving outcomes.
