Pericytes mediate neuroinflammation via Fli-1 in endotoxemia and sepsis in mice.

Summary

Using endotoxemia and CLP models with pericyte-specific Fli-1 deletion, the authors show that Fli-1 upregulation in brain pericytes drives MCP-1 and IL-6 expression and microglial activation during sepsis. LPS induces Fli-1 via TLR4-MyD88, positioning pericyte Fli-1 as a mechanistic node and potential therapeutic target for sepsis-associated encephalopathy.

Key Findings

• Fli-1 levels increase rapidly in brain pericytes after LPS and in brain tissue after CLP.
• Pericyte-specific Fli-1 knockout reduces MCP-1 and IL-6 expression and attenuates microglial activation.
• LPS induces Fli-1 via TLR4-MyD88 signaling, which elevates MCP-1 production in pericytes.
• Pericyte Fli-1 is a candidate therapeutic target for sepsis-associated neuroinflammation.

Clinical Implications

While preclinical, targeting Fli-1 or downstream MCP-1/IL-6 signaling in pericytes could offer strategies to prevent or mitigate sepsis-associated encephalopathy.

Limitations

• Preclinical mouse and cell models without human validation.
• Focus on early inflammatory readouts; effects on long-term neurological outcomes or survival were not reported.

Future Directions

Validate Fli-1 modulation in human tissues/CSF, assess behavioral and survival outcomes in sepsis models, and explore pharmacologic Fli-1 inhibitors or MCP-1/IL-6 pathway blockade.