Related Experiment Video
Updated: Jun 14, 2025
Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex
Published on: August 2, 2021
CD14 is a decision-maker between Fas-mediated death and inflammation
Zoie Magri1, David Jetton1, Hayley I Muendlein2
1Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111, USA.
Abstract:
Signaling through classical death receptor Fas was mainly appreciated as a pro-death pathway until recent reports characterized pro-inflammatory outcomes of Fas-mediated activation in pathological contexts. How Fas signaling can switch to pro-inflammatory activation is poorly understood. Herein, we report that in macrophages and neutrophils, the Toll-like receptor (TLR) adapter CD14 determines the inflammatory output of Fas-mediated signaling. Our findings propose CD14 as a crucial chaperone of Fas receptor internalization in macrophages and neutrophils, resulting in Cd14-/- myeloid cells that are protected from FasL-induced apoptosis, activate nuclear factor κB (NF-κB), and release cytokines in response. As in TLR signaling, CD14 is also required for Fas to signal through the adaptor TRIF (TIR-domain-containing adapter-inducing interferon-β) and induce a pro-death complex. Our findings demonstrate that CD14 availability can determine the switch between Fas-mediated pro-death and pro-inflammatory outcomes by internalizing the receptor.
Insights
CD14 controls Fas receptor signaling, switching it between pro-death and pro-inflammatory responses in immune cells. This discovery reveals CD14
Area of Science:
- Immunology
- Cell Biology
Background:
- Fas receptor signaling was traditionally viewed as a pro-death pathway.
- Recent studies suggest Fas can also mediate pro-inflammatory responses in disease.
- The mechanisms governing this switch in Fas signaling remain unclear.
Purpose of the Study:
- To investigate the role of CD14 in modulating Fas-mediated signaling outcomes.
- To elucidate how Fas signaling switches between pro-death and pro-inflammatory pathways.
Main Methods:
- Utilized myeloid cells (macrophages and neutrophils) lacking CD14 (Cd14-/-).
- Analyzed Fas receptor internalization and downstream signaling pathways.
- Assessed NF-κB activation and cytokine release following FasL stimulation.
Main Results:
- CD14 deficiency protected myeloid cells from FasL-induced apoptosis.
- Cd14-/- myeloid cells exhibited increased NF-κB activation and cytokine production.
- CD14 was essential for Fas-mediated signaling through TRIF, including pro-death complex formation.
Conclusions:
- CD14 acts as a critical regulator of Fas receptor internalization.
- CD14 availability determines whether Fas signaling results in cell death or inflammation.
- Targeting CD14 could modulate Fas-mediated immune responses in pathological conditions.
More Related Videos
Related Concept Videos
01:17The Extrinsic Apoptotic Pathway
01:38Inflammation