As part of the body's first line of defense against foreign invaders, macrophages play an integral role in the innate immune system. However, the ability of macrophages to interpret and respond to diverse danger signals remains incompletely understood. Researchers from the University of Manchester have now found that increases in cell volume reprogram macrophage gene expression and induce inflammation. The findings, to be published May 7 in the Journal of Cell Biology (JCB), add another piece to the ever-expanding puzzle of immune-related inflammatory responses.
Macrophages are some of the first responders to both invading pathogens and tissue damage. These specialized cells can detect an extensive catalogue of both intra- and extracellular danger signals, leading to the initiation and sustainment of inflammatory responses. Notably, macrophages also possess the ability to tune the nature of their response depending on the type of insult sensed in order to neutralize the threat in the most appropriate way. But many questions remain as to how these tailored responses occur.
One phenomenon that has risen in prominence in recent years is the influence of physical forces on immune responses. For example, it has been shown that the loss of a cell's ability to control its volume due to the dysregulation of proteins like the Volume Regulated Anion Channel (VRAC) can lead to activation of danger-sensing pathways of the innate immune system, and subsequently, inflammation.
"Despite the reported indications that cell volume and VRAC are involved in inflammatory signaling, the basic biological mechanisms of how the regulation of cell volume shapes inflammation were unknown," says Jack Green, a Research Fellow at the University of Manchester and senior author of the new JCB study.
Green's team examined macrophages that lack the VRAC protein and swell up when placed in a mild hypoosmotic environment. The group found that cell swelling resulted in a dramatic change in the expression levels of various genes, including an increase in many genes involved in inflammatory signaling pathways. Their data predicted that the proteins most likely to be activated upon cell swelling were all core components of antiviral and proinflammatory signaling or nucleic acid–sensing pathways.
"Together, these findings suggest that cell volume acts as an additional layer of danger sensing in macrophages that shapes and tunes the nature of immune responses to pathogens," first author James Cook says. Indeed, upon treatment of VRAC-deficient macrophages, which cannot control their volume, with Influenza A virus, the cells demonstrated an enhanced antiviral response as compared to their wild-type counterparts.
With promising in vitro data in hand, Cook and colleagues used a mouse model of systemic hyperinflammation to ask how their results would translate in vivo. The team observed that, compared to wild-type mice undergoing systemic inflammation, the levels of a key, proinflammatory signaling molecule were significantly increased in VRAC-deficient mice. This indicates that macrophages with dysregulated cell volumes do, in fact, contribute to aberrant inflammatory responses.
The results from this study have established changes in cell volume as a signal that acts together with other stimuli to modify and shape inflammatory responses. "Understanding disruptions in the tissue microenvironment leading to alterations in cell volume is therefore an important consideration in our understanding of inflammation and disease pathogenesis," concludes Green, adding that "future studies will reveal the potential for regulating VRAC-dependent cell volume changes in macrophages in disease."
Cook et al., 2026. J. Cell Biol. https://rupress.org/jcb/article-lookup/doi/10.1083/jcb.202411133?PR
