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Background <p>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.</p> Methods <p>WT and pericyte-specific <i>Fli-1</i> knockout mice were subjected to endotoxemia through LPS injection or sepsis via cecal ligation and puncture (CLP). In vitro, <i>Fli-1</i> was knocked down using small interfering RNA in cultured mouse brain pericytes, followed by LPS stimulation.</p> Results <p>Elevated <i>Fli-1</i> levels were observed in isolated brain pericytes 2&#xa0;h after LPS administration, in brain tissues 4&#xa0;h after CLP, and in cultured mouse brain pericytes 2&#xa0;h after LPS stimulation in vitro. In endotoxemic mice, pericyte-specific <i>Fli-1</i> knockout reduced expression of MCP-1 and IL-6 in brain tissue 2&#xa0;h after LPS injection. At 24&#xa0;h post-LPS administration, protein levels of MCP-1 and IL-6, and microglia activation were suppressed in pericyte-<i>Fli-1</i> knockout mice. Additionally, <i>Fli-1</i> deficiency in pericytes significantly reduced MCP-1 and IL-6 mRNA levels in the brain tissue 4&#xa0;h after CLP. Moreover, in cultured brain pericytes, <i>Fli-1</i> knockdown markedly decreased MCP-1 and IL-6 levels after LPS stimulation. Notably, LPS stimulation increased <i>Fli-1</i> levels via TLR4-Myd88 signaling, which subsequently led to elevated production of MCP-1 in brain pericytes.</p> Conclusions <p><i>Fli-1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月25日

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  • Pengfei Li,
  • Liu Liu,
  • Perry V. Halushka,
  • Maria Trojanowska,
  • Guirong Wang,
  • Adviye Ergul,
  • Hongkuan Fan

摘要

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.