The multifaced personality of intestinal CX3CR1+ macrophages

Intestinal macrophages expressing the fraktalkine receptor (CX3CR1+) represent a cell population that plays a variety of roles ranging from maintaining intestinal immune homeostasis at steady state to controlling antigen access by extending transepithelial dendrites (TEDs) to capture luminal microbes and shuttle them across the epithelium to initiate immune responses. However, recent evidence shows that very early during infection, pathogen-capturing CX3CR1+ macrophages migrate to the lumen of the small intestine, therefore preventing pathogens from traversing the epithelium. Here we discuss the complexity of the at-times seemingly opposing roles played by these cells and propose that CX3CR1-mediated pathogen exclusion is part of a defensive strategy against infections that includes multiple effector mechanisms acting synergistically at the intestinal mucosa. Intestinal macrophages expressing the fraktalkine receptor (CX3CR1+) play a variety of roles at the host–microbe interface in the gut. CX3CR1+ macrophages originate from Ly6Chi precursors and contribute to the maintenance of intestinal immune homeostasis. CX3CR1+ macrophages can sample antigen and migrate back to the lymph node, but also transmigrate to the lumen of the gut following pathogen uptake. The intraluminal transmigration of CX3CR1+ macrophages significantly reduces the pathogen burden in the intestinal tissue, thus acting as a rapidly deployed mechanism of pathogen exclusion. CX3CR1+ macrophage-mediated antigen sampling and intraluminal migration occur in different areas of the gut and are triggered by different regulatory signals.