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Updated: Aug 2, 2025
Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
Inflammatory macrophage to hepatocyte signals can be prevented by extracellular vesicle reprogramming
Priyanka Ghosh1,2, Kyo Sasaki1,2, Isabel Aranzazu Pulido Ruiz1,2
1Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Abstract:
Macrophage-derived extracellular vesicles (EVs) play key roles in intercellular communication. Within the liver, they have been linked to several inflammatory diseases including nonalcoholic fatty liver disease (NAFLD). In this study, we found that inflammatory macrophages cause injury to hepatocytes, in part by a cell-cell crosstalk phenomenon involving the secretion of EVs containing pro-inflammatory cargo. Incorporation of these inflammatory signals into EV requires the cleavage of the trafficking adaptor protein RILP, which, as previously shown, results from inflammasome-mediated caspase-1 activation. RILP cleavage can be blocked by overexpressing a dominant negative, non-cleavable form of RILP (ncRILP). EV preparations from ncRILP-expressing cells are, by themselves, sufficient to suppress inflammatory effects in hepatocytes. These results suggest that both direct RILP manipulation and/or supplying ncRILP-modified EVs could be used as a novel therapy for the treatment of inflammatory liver diseases.
Insights
Inflammatory macrophages release extracellular vesicles (EVs) that harm liver cells. Blocking RILP protein cleavage in these EVs may offer a new therapy for inflammatory liver diseases like NAFLD.
Area of Science:
- Cell Biology
- Immunology
- Hepatology
Background:
- Macrophage-derived extracellular vesicles (EVs) are critical mediators of intercellular communication.
- In the liver, macrophage EVs are implicated in inflammatory conditions such as nonalcoholic fatty liver disease (NAFLD).
Purpose of the Study:
- To investigate the role of macrophage-derived EVs in hepatocyte injury.
- To identify molecular mechanisms regulating the pro-inflammatory cargo of these EVs.
- To explore therapeutic strategies targeting EV-mediated liver inflammation.
Main Methods:
- Utilized cell culture models of inflammatory macrophages and hepatocytes.
- Investigated the role of the trafficking adaptor protein RILP and its cleavage by caspase-1.
- Employed dominant-negative, non-cleavable RILP (ncRILP) overexpression to block RILP cleavage.
- Analyzed the functional effects of EVs derived from ncRILP-expressing cells on hepatocytes.
Main Results:
- Inflammatory macrophages induce hepatocyte injury via EVs containing pro-inflammatory cargo.
- Cleavage of RILP, mediated by inflammasome-activated caspase-1, is essential for loading inflammatory signals into EVs.
- Overexpression of ncRILP prevents RILP cleavage and subsequent EV-mediated inflammation.
- EVs derived from ncRILP-expressing cells demonstrated suppressive effects on inflammatory responses in hepatocytes.
Conclusions:
- Macrophage EVs contribute to liver inflammation and injury through RILP-dependent mechanisms.
- Targeting RILP cleavage or utilizing ncRILP-modified EVs presents a potential therapeutic avenue for inflammatory liver diseases.
- This study highlights a novel mechanism of intercellular communication in liver inflammation and identifies a potential therapeutic target.
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