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Published on: April 13, 2017
CD14 is a key organizer of microglial responses to CNS infection and injury
Hana Janova1, Chotima Böttcher2, Inge R Holtman3
1Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
Abstract:
Microglia, innate immune cells of the CNS, sense infection and damage through overlapping receptor sets. Toll-like receptor (TLR) 4 recognizes bacterial lipopolysaccharide (LPS) and multiple injury-associated factors. We show that its co-receptor CD14 serves three non-redundant functions in microglia. First, it confers an up to 100-fold higher LPS sensitivity compared to peripheral macrophages to enable efficient proinflammatory cytokine induction. Second, CD14 prevents excessive responses to massive LPS challenges via an interferon β-mediated feedback. Third, CD14 is mandatory for microglial reactions to tissue damage-associated signals. In mice, these functions are essential for balanced CNS responses to bacterial infection, traumatic and ischemic injuries, since CD14 deficiency causes either hypo- or hyperinflammation, insufficient or exaggerated immune cell recruitment or worsened stroke outcomes. While CD14 orchestrates functions of TLR4 and related immune receptors, it is itself regulated by TLR and non-TLR systems to thereby fine-tune microglial damage-sensing capacity upon infectious and non-infectious CNS challenges.
Insights
CD14 enhances microglial sensitivity to LPS and prevents over-responses, while being essential for sensing damage. CD14 deficiency in microglia disrupts CNS immune balance during infection and injury.
Area of Science:
- Neuroimmunology
- Innate Immunity
- Central Nervous System (CNS) Biology
Background:
- Microglia are innate immune cells in the CNS, crucial for sensing infection and damage.
- Toll-like receptor (TLR) 4, a key sensor, recognizes bacterial lipopolysaccharide (LPS) and injury signals.
- CD14 acts as a co-receptor for TLR4, modulating microglial responses.
Purpose of the Study:
- To elucidate the non-redundant functions of CD14 in microglial responses to CNS challenges.
- To investigate CD14's role in modulating LPS sensitivity, preventing excessive inflammation, and sensing damage-associated signals.
- To understand the impact of CD14 deficiency on CNS immune balance during infection and injury.
Main Methods:
- In vivo studies using mouse models of bacterial infection, traumatic brain injury, and ischemic stroke.
- Assessment of microglial activation, cytokine induction, and immune cell recruitment.
- Analysis of CD14's role in LPS sensitivity and interferon-beta mediated feedback.
- Evaluation of microglial responses to tissue damage-associated signals.
Main Results:
- CD14 confers up to 100-fold higher LPS sensitivity in microglia compared to peripheral macrophages, enabling efficient proinflammatory cytokine induction.
- CD14 prevents excessive microglial responses to high LPS doses through interferon-beta feedback.
- CD14 is essential for microglial sensing of tissue damage-associated signals.
- CD14 deficiency in mice leads to imbalanced CNS responses, including altered inflammation, immune cell recruitment, and worsened stroke outcomes.
Conclusions:
- CD14 plays critical, non-redundant roles in microglial function, including heightened LPS sensitivity, regulation of inflammatory intensity, and damage sensing.
- These CD14-mediated functions are vital for maintaining CNS immune homeostasis during infectious and non-infectious challenges.
- Dysregulation of CD14 impacts CNS immune balance, highlighting its therapeutic potential in neurological disorders.
