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Regulation of CD14 expression on human adult central nervous system-derived microglia
B Becher1, V Fedorowicz, J P Antel
1Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Abstract:
Microglial cells function as regulators of immune reactivity within the CNS and may contribute to tissue injury under inflammatory conditions. Such functions are correlated with their state of activation. In this study, we report the de novo expression of CD14 by adult human CNS-derived microglia which acquire a bipolar activated morphologic phenotype in dissociated tissue culture. Surface CD14 expression can be down-regulated by interaction with its ligand lipopolysaccharide (LPS), and by the T-helper (Th1) cytokine interferon-gamma (IFN-gamma) or the Th2 cytokine interleukin-4 (IL-4). Semiquantitative polymerase chain reaction (PCR) analysis of CD14 mRNA expression under each condition suggests a different mechanism accounting for the reduced surface expression. LPS down-regulates CD14 mRNA, consistent with a feed-back signal preventing over-stimulation. IFN-gamma augments CD14 transcription, suggesting cleavage of surface CD14 consequent to general cell activation. IL-4 decreases mRNA production likely reflecting a generalized suppressive effect. The effect of LPS, IFN-gamma and IL-4 on CD14 expression differes from their effect on expression of the immune-accessory molecules B7-1 and HLA-DR, and on production of tumor necrosis factor-alpha (TNF-alpha), whose secretory pathway is similar to that of CD14. These results indicate the selective effects of molecules, likely to be present in the infected or inflamed CNS, on regulating CD14 expression and that there can be differential regulation of immune response relevant molecules expressed by activated microglia.
Insights
Activated microglia express CD14, a key immune regulator in the central nervous system (CNS). Lipopolysaccharide (LPS) and cytokines like interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) differentially regulate CD14 expression and mRNA levels.
Area of Science:
- Neuroimmunology
- Cellular immunology
- Molecular biology
Background:
- Microglial cells are key immune regulators in the central nervous system (CNS).
- Microglial activation state influences immune responses and potential tissue damage in inflammatory CNS conditions.
- Understanding microglial immune molecule regulation is crucial for neuroinflammatory research.
Purpose of the Study:
- To investigate the de novo expression of CD14 in adult human CNS-derived microglia.
- To determine how lipopolysaccharide (LPS) and specific cytokines (IFN-gamma, IL-4) modulate CD14 surface expression and mRNA levels.
- To explore the differential regulation of CD14 compared to other immune molecules like B7-1, HLA-DR, and TNF-alpha.
Main Methods:
- Culturing adult human CNS-derived microglia.
- Assessing CD14 surface expression via immunofluorescence.
- Quantifying CD14 mRNA levels using semiquantitative polymerase chain reaction (PCR).
- Analyzing the effects of LPS, IFN-gamma, and IL-4 on CD14 expression and mRNA.
Main Results:
- Adult human microglia de novo express CD14 in culture, adopting an activated phenotype.
- LPS down-regulates CD14 mRNA, suggesting feedback inhibition.
- IFN-gamma augments CD14 transcription, potentially via cleavage of surface CD14.
- IL-4 decreases CD14 mRNA production, indicating a suppressive effect.
- Regulation of CD14 differs from that of B7-1, HLA-DR, and TNF-alpha.
Conclusions:
- Microglia selectively regulate CD14 expression in response to CNS inflammatory molecules.
- Differential regulation of immune molecules like CD14 by LPS, IFN-gamma, and IL-4 highlights complex microglial immune responses.
- These findings offer insights into the nuanced control of immune responses within the inflamed or infected CNS.
