Cells that die during inflammation send messages that promote healing, study finds

A study by the team of Professor Kodi Ravichandran (VIB-UGent Center for Inflammation Research) and colleagues has revealed that pyroptosis, a form of programmed cell death traditionally considered purely inflammatory, also plays a crucial role in promoting tissue healing and repair. This research, published in Natureopens new avenues for understanding how our bodies respond to injury and could lead to innovative treatments for wounds and inflammatory diseases.

Every day, about a billion cells die in our body. Most of these cells are killed by a process called apoptosis, a form of cellular maintenance that keeps us healthy. However, under the influence of pathogens or inflammatory triggers, cells can die in a process called pyroptosis.

As the name suggests (pyro means fire), pyroptosis causes significant inflammation, which helps the body clear infections, but also causes severe tissue damage.

“Cell death by pyroptosis has so far only been considered an inflammatory and damaging disease, but our work suggests that in addition to tissue-damaging factors, pyroptosis also releases beneficial molecules that promote wound healing, which could lead to new treatments for treating chronic wounds or inflammation,” says Professor Kodi Ravichandran (VIB-UGent), one of the lead authors of this study.

Inflammation and healing

Whenever we encounter an injury or infection, our body responds by triggering an immune response that results in inflammation that clears the infection. However, when inflammation is not resolved in a timely or controlled manner, excessive tissue damage can occur. Cells undergoing pyroptosis contribute to this inflammation by releasing inflammatory molecules.

However, new research by Professor Kodi Ravichandran’s team and colleagues reveals that these pyroptotic cells also release molecules that can promote wound healing.

“To our surprise, using cell culture and mouse model systems, the molecules secreted by pyroptotic cells are unique. These molecules induce significant changes in the gene expression of neighboring healthy immune cells (macrophages) that promote tissue healing and repair,” says Dr. Parul Mehrotra, lead and first author of the study (VIB-UGent, now at the Indian Institute of Technology, Delhi).

“So pyroptosis presses both the accelerator and the brake; on the one hand, inflammatory cytokines released by pyroptotic cells cause inflammation, while metabolites and oxylipins in the secretome help the tissue heal.”

Wound closure

One of the key wound healing molecules identified by the researchers is prostaglandin E2, known for its role in pain and tissue regeneration.

Dr Sophia Maschalidi (VIB-UGent), co-first author of the work, says: “Our experiments revealed that molecules secreted by dying cells, known as the pyroptotic secretome, can significantly increase the body’s ability to repair damaged tissue, even when inflammatory molecules are present.”

This study suggests that current strategies aimed at developing treatments by blocking pyroptosis need to be reconsidered. While this approach can prevent injury, it could also inhibit the release of molecules essential for tissue repair.

Instead, the newly identified small molecules and lipids of the pyroptotic secretome could be harnessed to develop novel therapies, offering new hope to patients suffering from chronic wounds or inflammatory diseases.