Like policemen patrolling a residential estate, immune cells known as macrophages can be found within tissues and organs, constantly keeping a lookout for foreign microbes and rogue cells. After an inflammatory response, these tissue-resident macrophages (RTMs) may need to be replenished.
Some replacement RTMs are thought to be derived from monocytes—another type of immune cell circulating in the blood. However, without a way to track monocytes and their precursors as they mature, researchers found it difficult to estimate the relative contribution of circulating monocytes to RTM numbers.
Now, scientists led by Florent Ginhoux, a Senior Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN), have discovered a gene (or marker) that faithfully maps the development path of monocytes. Working with colleagues in China and Germany, Ginhoux’s team profiled immune cells and found that Ms4a3 was specifically expressed by monocyte-committed progenitor cells—precursor cells that are fated to become monocytes.
“One can think of Ms4a3 as a switch that is only turned on in monocyte-committed progenitor cells,” Ginhoux said.
The researchers also demonstrated that macrophages themselves do not express Ms4a3. This was an important finding because it meant that any RTMs expressing Ms4a3 originated from monocyte-committed progenitor cells.
Using Ms4a3 as a marker, Ginhoux’s team was able to quantify the extent to which monocytes contributed to RTMs in various organs. In a mouse model of inflammation, the researchers reported that the proportion of Ms4a3-expressing circulating monocytes decreased while the proportion of Ms4a3-expressing RTMs increased as inflammation progressed. This suggested that circulating monocytes were recruited to the site of inflammation, where they subsequently matured into RTMs. The researchers further noted that factors such as sex, age and diet impact the extent of monocyte contribution to RTMs.
Ginhoux added that the discovery of specific immune cell markers such as Ms4a3 will pave the way for a more holistic understanding of the immune system. “Rather than define immune cell populations only by their function, we can now also define them by their origins, since we can trace their lineage and map their fates,” he explained.
This broader definition could offer clues into the body’s immunological responses to cancer, something that Ginhoux is keen to explore in the future. “We already have clear evidence that tumor-associated macrophages play an important role in the progression of mouse and human cancers. By exploring the origins of those immune cell populations, we may be able to better target them to treat cancer,” he said.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN).