When bacteria or viruses invade, the body’s ability to rapidly deploy white blood cells to attack the invader is a remarkable biological feat. But these rapid-attack cells, called myeloid cells, ideally work only as first responders to keep a pathogen contained. When responding to an infection, they are generally short-lived, followed by other specialized types of immune cells, for good reason.
“Because these cells are quite unspecific in their mechanism of action, they do kill and contain bacteria, but they also generate a lot of damage in the surrounding tissue,” said Jorge Henao-Mejia, MD, PhD, an assistant professor of Pathology and Laboratory Medicine at The Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania. “For that reason, these cells are involved not only in the immunopathology after infection, but also in every chronic human disease that has an inflammatory component, such as obesity, cancer, asthma, you name it.”
Keeping those short-lived but destructive cells under control is therefore a desirable approach for reducing the harm associated with those inflammatory processes. Thanks to Dr. Henao-Mejia and his collaborators, scientists are now a step closer to doing that.
They have identified how, at the molecular level, the body regulates the short lifespan of myeloid cells, specifically eosinophils, neutrophils, and monocytes. Published in Nature in August, the team’s findings from in vitro studies and a genetically modified mouse model have implications for finding future therapies that act on the equivalent molecular pathways in human disease, especially inflammatory disorders.
“Despite the fact that, for more than 70 or 80 years it has been known that these cells exist and live only a short time, the molecular mechanism of how the lifespan of these cells is actually regulated was pretty much unknown,” Dr. Henao-Mejia said. “So I think we found a pretty important clue of how this is working.”
The first steps toward this discovery began during Dr. Henao-Mejia’s postdoctoral fellowship at Yale University. He led the discovery there of a gene that codes for an RNA molecule they named Morrbid (MyelOid RNA Regulator of Bim-Induced Death). This molecule is a long non-coding RNA, a type of molecule that cells produce by transcribing DNA into RNA that is not then translated into the production of a protein. Such molecules are the products of about 70 percent of the human genome, and the majority of their functions are unknown. (That fact may come as a surprise to those who learned the “central dogma” of biology over the past several decades, that genes code for RNA which is used to produce proteins; only about 2 percent of the human genome codes for proteins in this way.) The team at Yale also genetically engineered a mouse model that lacked Morrbid.
When Dr. Henao-Mejia started his own lab at CHOP in 2014, he led continuing studies of this molecule with several of his students. The team found that eosinophils, neutrophils, and monocytes were the specific types of cells that highly expressed Morrbid, and they discovered how it is involved in the tightly and rapidly regulated death of these cells. Essentially, when the body releases immune signaling molecules that support myeloid cell survival, these signals induce Morrbid. Morrbid, in turn, blocks the expression of a nearby “death” gene called Bim. In the absence of Morrbid, Bim regulates the programmed death of the cell — and this is what happens when survival signals are absent from the periphery and Morrbid is no longer expressed. Because the two genes, Morrbid and Bim, are nearly adjacent to each other in the DNA sequence, Morrbid can control Bim and the cell’s death process extremely rapidly. That is exactly what the body would need to retain precise control over the lifespan of myeloid cells.
Next, taking a step toward translating this finding from mice to humans, Dr. Henao-Mejia and colleagues looked at cells from human patients with hypereosinophilic syndrome, a group of inflammatory disorders often involving overactive eosinophils. In these cells, the human version of the long non-coding RNA, MORRBID, was indeed overexpressed.
“What this provides is an entry point to try to regulate inflammatory conditions by simply targeting this RNA,” Dr. Henao-Mejia said.
Dr. Henao-Mejia sees several next steps as key to translating these findings into a possible human therapy. One step will be to identify whether Morrbid regulates cell death in other types of immune cells beyond those identified in the experiments to date. In addition, he needs to more definitively confirm what his current human-cell finding implies — that the human RNA MORRBID has the same function as the mouse RNA Morrbid used in the majority of his team’s experiments. If it does, he will move toward developing molecules that have potential use as therapies to inhibit this RNA, allowing the body to more rapidly shut down its destructive immune cells when they are harming more than helping.