How Macrophages Use Cell Swelling to Detect and Fight Infections

A new study from the University of Manchester has uncovered how macrophages—key cells in the immune system—use changes in cell volume to detect danger. The findings, due to be published in the Journal of Cell Biology on 7 May 2026, reveal that swelling in these cells triggers a strong inflammatory and antiviral response. Until now, the exact ways macrophages sense and react to threats have remained unclear.

Macrophages play a vital role in the body’s first line of defence against infection and injury. Researchers discovered that when these cells swell, hundreds of genes linked to type I interferon signalling, nucleic acid detection, and inflammation become highly active. This suggests that cell volume acts as an extra sensor, helping macrophages adjust their response to different threats.

The study focused on macrophages lacking a channel called VRAC (Volume Regulated Anion Channel). When exposed to low-salt conditions, these cells swelled rapidly, leading to major shifts in gene activity. Tests in mice showed that VRAC-deficient animals produced far higher levels of inflammatory molecules during systemic inflammation, linking cell swelling to stronger immune reactions. Further experiments found that VRAC-deficient macrophages also mounted a more aggressive response to Influenza A virus in lab conditions. They produced more interferon and antiviral proteins, indicating that cell volume directly influences how macrophages fight infections. Protein network analyses supported this, showing that swelling activates core pathways involved in detecting viruses and danger signals.

The research highlights cell volume as a previously overlooked factor in macrophage function. By sensing swelling, these immune cells may fine-tune their reactions to infections or tissue damage. The findings could help explain how immune responses are regulated at a molecular level, with potential implications for treating inflammatory diseases.