Intestinal macrophages expressing the fraktalkine receptor CX3CR1+ is a cell population that plays a variety of critical roles ranging from maintaining intestinal immune homeostasis at steady state to controlling antigen access by extending transepithelial dendrites to capture luminal microbes and shuttle them across the epithelium to initiate immune responses. Yet, recently it has emerged that very early during infection a rapid intraluminal migration of pathogen-capturing CX3CR1+ macrophages occurs in the small intestine that helps preventing pathogens from traversing the epithelium. Here we discuss the complexity of, at times seemingly opposing roles played by these cells and propose that the CX3CR1-mediated pathogen-exclusion is part of a defensive strategy against infections that includes multiple effector mechanisms acting synergistically at the intestinal mucosal.
