Guarding Life: How Calcium Transforms Cell Death Into Defense

Researchers at Kyushu University have discovered a vital role for calcium in getting rid of dead cells in our body’s protective tissues.

This finding is crucial for understanding how our bodies keep the outer and inner surfaces clean and safe from infection. The study, using advanced techniques, shows that when cells in these protective layers die, calcium helps the neighboring cells quickly remove them, maintaining a healthy barrier.

Discovery of a New Cellular Mechanism

Researchers at Kyushu University in Japan have uncovered a calcium-driven process crucial for removing dead cells, enhancing our understanding of how our bodies maintain health and prevent disease. Published recently in the journal Current Biology, their findings show that calcium ion levels are vital for effectively clearing dying cells, known as apoptotic cells, from epithelial tissues—these are the cells that form protective linings on body surfaces. The study utilized genetically modified epithelial tissue cultures, along with molecular markers and sophisticated imaging techniques to observe this process.

Vital Barriers and Cellular Defense

Epithelial cells cover the outer and inner surfaces of our bodies, including the skin and internal organs, serving as essential protective barriers. When these cells become damaged and die, a process known as apoptosis, adjacent cells quickly collaborate to eject the dead cells and close any openings. This action helps prevent the entry of harmful substances that could lead to infections or inflammation. While this process is critical for maintaining the integrity of epithelial barriers, the detailed mechanisms involved were not fully understood until this recent discovery.

The study, led by Professor Junichi Ikenouchi and his colleagues, Dr. Kenji Matsuzawa and Mr. Yuma Cho, the first author, from Kyushu University, also included contributions from collaborators from the University of Tokyo and Health Sciences University of Hokkaido in Japan.

Introduction to CaRE: A Calcium Response Mechanism

To begin with, the team induced apoptosis in individual epithelial cells using a focused laser and observed the response in the surrounding cells. They then observed how nearby cells reacted by modifying them to express special calcium ion probes called GCaMP6, which allowed them to visualize real-time calcium changes. Interestingly, they found that the neighbors of the apoptotic cell showed a significant spike in calcium levels, particularly near the membrane regions interfacing with the dying cell. The researchers named this intriguing phenomenon the “calcium response in effectors of apical extrusion (CaRE).”

Role of IP3 Receptors and Desmosomes in Cell Removal

Delving deeper into this newly discovered mechanism, the team next examined the role of IP3 receptors, proteins present inside cells that help regulate calcium ion levels. They found that inhibiting the activity of IP3 receptors or removing their associated genes completely prevented the expulsion of apoptotic cells. Further analysis using advanced electron microscopy revealed that a specific subset of IP3 receptors, particularly those located near desmosomes, plays a key role in CaRE.

Desmosomes are cell adhesion structures that form strong connections between cells, acting like buttons that hold them together. They are especially important in tissues like skin and organ linings, helping to keep everything intact and functioning properly. By ensuring neighboring cells adhere tightly, desmosomes play a key role in maintaining the structure and stability of our body’s tissues. The team found that the activation of IP3 receptors near desmosomes is necessary for triggering the contraction of a group of proteins known as actomyosin complex, which helps cells change shape and move, facilitating the removal of apoptotic cells. “Our study sheds light on a newfound role of IP3 receptors in desmosomes, the latter of which were previously thought to be involved only in mechanical connections between epithelial cells,” highlights Ikenouchi.

As this study was conducted on cultured cells, the team notes that further analysis of the CaRE mechanism is needed to determine whether the mechanism also functions in living organisms, if it varies between different organ tissues, and whether other factors also play a role.

Overall, this study advances our understanding of how our bodies maintain a healthy epithelium—something many of us take for granted. “Our findings provide valuable insights into understanding diseases caused by epithelial barrier disruption, such as atopic dermatitis and inflammatory bowel disease, and may contribute to the development of new preventive measures and treatments for chronic inflammation,” concludes Ikenouchi.

Reference: “A sustained calcium response mediated by IP3 receptor anchoring to the desmosome is essential for apoptotic cell elimination” by Yuma Cho, Ikuko Koyama-Honda, Akihiko Tanimura, Kenji Matsuzawa and Junichi Ikenouchi, 23 September 2024, Current Biology.
DOI: 10.1016/j.cub.2024.08.057