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Pericytes mediate neuroinflammation via Fli-1 in endotoxemia and sepsis in mice
Pengfei Li1, Liu Liu1, Perry V Halushka2
1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC, 29425, USA.
Background:
Sepsis-associated encephalopathy (SAE) often results from neuroinflammation. Recent studies have shown that brain platelet-derived growth factor receptor β (PDGFRβ) cells, including pericytes, may act as early sensors of infection by secreting monocyte chemoattractant protein-1 (MCP-1), which transmits inflammatory signals to the central nervous system. The erythroblast transformation-specific (ETS) transcription factor Friend leukemia virus integration 1 (Fli-1) plays a critical role in inflammation by regulating the expression of key cytokines, including MCP-1. However, the role of pericyte Fli-1 in neuroinflammation during sepsis remains largely unknown.
Methods:
WT and pericyte-specific Fli-1 knockout mice were subjected to endotoxemia through LPS injection or sepsis via cecal ligation and puncture (CLP). In vitro, Fli-1 was knocked down using small interfering RNA in cultured mouse brain pericytes, followed by LPS stimulation.
Results:
Elevated Fli-1 levels were observed in isolated brain pericytes 2 h after LPS administration, in brain tissues 4 h after CLP, and in cultured mouse brain pericytes 2 h after LPS stimulation in vitro. In endotoxemic mice, pericyte-specific Fli-1 knockout reduced expression of MCP-1 and IL-6 in brain tissue 2 h after LPS injection. At 24 h post-LPS administration, protein levels of MCP-1 and IL-6, and microglia activation were suppressed in pericyte-Fli-1 knockout mice. Additionally, Fli-1 deficiency in pericytes significantly reduced MCP-1 and IL-6 mRNA levels in the brain tissue 4 h after CLP. Moreover, in cultured brain pericytes, Fli-1 knockdown markedly decreased MCP-1 and IL-6 levels after LPS stimulation. Notably, LPS stimulation increased Fli-1 levels via TLR4-Myd88 signaling, which subsequently led to elevated production of MCP-1 in brain pericytes.
Conclusions:
Fli-1 in pericytes may serve as a crucial mediator of neuroinflammation during sepsis by directly regulating pivotal cytokines such as MCP-1 and IL-6. Therefore, Fli-1 has the potential to serve as a therapeutic target in SAE and other neuroinflammatory disorders.
Insights
Friend leukemia virus integration 1 (Fli-1) in brain pericytes drives neuroinflammation in sepsis by regulating key cytokines. Targeting pericyte Fli-1 may offer a novel therapeutic strategy for sepsis-associated encephalopathy (SAE).
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Sepsis-associated encephalopathy (SAE) is a neuroinflammatory condition.
- Brain pericytes, expressing platelet-derived growth factor receptor β (PDGFRβ), sense infection and release inflammatory signals like monocyte chemoattractant protein-1 (MCP-1).
- The transcription factor Friend leukemia virus integration 1 (Fli-1) regulates inflammatory gene expression, but its role in pericytes during sepsis is unclear.
Purpose of the Study:
- To investigate the role of pericyte Fli-1 in neuroinflammation during sepsis.
- To determine if Fli-1 in pericytes regulates key inflammatory cytokines like MCP-1 and IL-6.
Main Methods:
- Used wild-type and pericyte-specific Fli-1 knockout mice subjected to LPS-induced endotoxemia or cecal ligation and puncture (CLP) sepsis models.
- Investigated Fli-1 expression and its downstream effects on MCP-1 and IL-6 in brain tissues and cultured pericytes.
- Utilized small interfering RNA (siRNA) to knock down Fli-1 in cultured mouse brain pericytes.
Main Results:
- Fli-1 expression increased in brain pericytes following LPS or CLP.
- Pericyte-specific Fli-1 knockout reduced MCP-1 and IL-6 expression and microglia activation in endotoxemic and septic mice.
- Fli-1 knockdown in cultured pericytes decreased MCP-1 and IL-6 production after LPS stimulation.
- LPS stimulation upregulated Fli-1 via TLR4-Myd88 signaling, promoting MCP-1 release from pericytes.
Conclusions:
- Pericyte Fli-1 is a key mediator of sepsis-induced neuroinflammation.
- Fli-1 directly regulates critical cytokines, including MCP-1 and IL-6, in brain pericytes.
- Pericyte Fli-1 represents a potential therapeutic target for SAE and other neuroinflammatory conditions.
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