Cell Volume Changes Found to Reprogram Immune Cells, Triggering Inflammation

Key Finding: Researchers at the University of Manchester discovered that increases in cell volume reprogram macrophage gene expression and induce inflammation.

The study, to be published May 7 in the Journal of Cell Biology (JCB), adds to our understanding of immune-related inflammatory responses. Macrophages are first responders to pathogens and tissue damage, and can detect various danger signals to initiate and sustain inflammatory responses.

Physical forces, such as cell volume changes, influence immune responses. Dysregulation of the Volume Regulated Anion Channel (VRAC) can activate danger-sensing pathways.

Experimental Results

Macrophages lacking the VRAC protein swelled in a mild hypoosmotic environment, leading to dramatic changes in gene expression, including increases in inflammatory signaling genes.

Predicted activated proteins upon cell swelling were core components of antiviral and proinflammatory signaling or nucleic acid–sensing pathways. VRAC-deficient macrophages treated with Influenza A virus showed enhanced antiviral response compared to wild-type cells.

In a mouse model of systemic hyperinflammation, VRAC-deficient mice had significantly increased levels of a key proinflammatory signaling molecule compared to wild-type mice.

Conclusion

Cell volume changes act as a signal that modifies inflammatory responses.

Understanding disruptions in the tissue microenvironment that lead to cell volume alterations is important for understanding inflammation and disease pathogenesis. Future studies may explore regulating VRAC-dependent cell volume changes in macrophages in disease.

Authors

• First author: James Cook
• Senior author: Jack Green, Research Fellow at University of Manchester