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Updated: Mar 16, 2026
Identifying Microglia and Peripheral Infiltrating Macrophages in the Injured Spinal Cords Using Flow Cytometry
Published on: June 24, 2025
SYK-dependent lipid handling in monocyte-derived macrophages governs functional recovery after spinal cord injury
Yuanzhe Zhao1, Hao Hu1, Jingwen Wang1
1Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Institute of Orthopaedics, Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China.
Abstract:
After spinal cord injury (SCI), monocyte-derived macrophages and resident microglia play critical, yet potentially distinct, roles in sculpting the lesion milieu via phagocytosis. However, the underlying mechanisms remain unclear. While spleen tyrosine kinase (SYK) has emerged as a master switch for microglial neuroprotection, its function in macrophages after SCI is unknown. Here, we show that SYK expression increases after SCI, peaking at 7 days post-injury (dpi) and persisting until 28 dpi, predominantly within Cx3cr1-GFP-F4/80+ macrophages rather than Cx3cr1-GFP+F4/80- microglia. Pharmacological blockade of SYK with intraperitoneal Entospletinib impaired macrophage phagocytosis, triggered intracellular lipid droplet accumulation, and impeded axonal regrowth and functional recovery. Conversely, SYK agonism with Pustulan injection boosted myelin phagocytosis, accelerated lipid metabolism, and enhanced locomotor outcomes. Notably, in triggering receptor expressed on myeloid cell 2 (TREM2) knockout mice, Pustulan treatment restored macrophage phagocytic competence and lipid droplet clearance, identifying TREM2-SYK signaling as the critical axis governing post-SCI macrophage function. Our findings establish SYK as a therapeutic target for reprogramming macrophage lipid metabolism and promoting repair following SCI.
Insights
Spleen tyrosine kinase (SYK) reprograms macrophages after spinal cord injury (SCI). Targeting SYK enhances myelin phagocytosis and promotes functional recovery by modulating macrophage lipid metabolism.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Macrophages and microglia are key in spinal cord injury (SCI) lesion formation via phagocytosis.
- Spleen tyrosine kinase (SYK) is known for microglial neuroprotection, but its role in SCI macrophages is unexplored.
Purpose of the Study:
- Investigate SYK's function in macrophages post-SCI.
- Determine SYK's role in macrophage-mediated phagocytosis, lipid metabolism, and functional recovery.
- Identify SYK's interaction with TREM2 signaling in SCI.
Main Methods:
- Assessed SYK expression in macrophages and microglia at various days post-SCI.
- Utilized SYK inhibitor (Entospletinib) and agonist (Pustulan) in SCI models.
- Examined phagocytosis, lipid droplet accumulation, and axonal regrowth.
- Investigated SYK function in TREM2 knockout mice.
Main Results:
- SYK expression increased in macrophages (not microglia) after SCI.
- SYK inhibition impaired phagocytosis and axonal repair, increasing lipid droplets.
- SYK agonism enhanced myelin phagocytosis, lipid metabolism, and locomotor recovery.
- TREM2-SYK axis was identified as crucial for macrophage function post-SCI.
Conclusions:
- SYK is predominantly expressed in macrophages post-SCI and regulates their function.
- Targeting SYK can reprogram macrophage lipid metabolism for enhanced SCI repair.
- The TREM2-SYK pathway is a critical therapeutic target for SCI.
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