Macrophages (green) in the intestine keep it healthy. Credit: Gross-Vered et al. (CC BY 4.0)
Macrophage cells play a crucial role in keeping the body free of disease-causing microbes and debris. They surveille the tissues, detect and clear infections, and tidy up dead cells. Most internal organs contain a population of macrophages that move into the organ during development and then persist throughout an organism’s life. However, tissues in contact with the outside world, such as the gut, need a constant supply of fresh macrophages. This supply depends on immune cells called monocytes moving into these tissues from the blood and maturing into macrophages when they arrive.
The macrophages in the gut have a challenging job to do. They need to be able to detect infections amongst healthy gut bacteria and foreign food particles. Macrophages from other tissues would overreact if they encountered this complicated environment, but gut macrophages learn to tolerate their surroundings by switching genes on and off as they mature. The exact combination of genes macrophages in the gut use depends on whether they are in the small or large intestine, which have different anatomies and resident microbes.
To understand how monocytes mature into macrophages in the gut, previous studies have focused on what happens during an infection. However, it remains unclear how monocytes develop into mature gut macrophages in the healthy gut. To address this question, Gross-Vered et al. have looked at mice in which gut macrophages can be killed when a drug is applied. This made it possible to replace the mice’s own macrophages with fluorescently labelled cells derived from monocytes.
Fluorescent monocytes were introduced into the bloodstream and arrived in the small and large intestine after the drug had been administered. Gross-Vered et al. then collected cells derived from these labelled monocytes and examined the genes that they were using. This revealed that once the monocytes entered the gut they began sensing their new environment and switching thousands of genes on and off. These changes happened rapidly at first and continued more gradually as the macrophages matured. Comparing the fluorescent macrophages from the small and large intestines revealed many similarities, but there were also hundreds of genes that differed. In the small intestine, macrophages switched on genes involved in catching and consuming bacteria, whereas macrophages in the large intestine, which has more resident healthy bacteria, turned on fewer of these bacteria-eating genes.
Inflammatory bowel disorders like ulcerative colitis and Crohn's disease both involve gut macrophages. Comparing the genes that macrophages use in the healthy and diseased gut may reveal information about these disorders. For example, ulcerative colitis only affects the large intestine, so understanding how and why the monocytes mature differently there could shed light on new ways to treat the disease.
