The Multifaceted 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.