Chemokine receptor expression defines a trajectory from monocytes to mature macrophages in the lung

CCR1, CCR2, and CCR5 direct recruitment of monocytes and macrophages in inflammation. However, the discrete role for each receptor in monocyte/macrophage biology remains poorly understood, with previous reports citing receptor redundancy. Using transcriptomic approaches to examine inflammatory chemokine receptor expression on lung interstitial macrophage populations, we demonstrate that interstitial macrophages can be divided into 3 distinct subsets, each of which express specific patterns of chemokine receptors, and that there are dynamic changes in chemokine receptor expression as macrophages differentiate from monocytes in the lung. Furthermore, macrophages expressing different combinations of chemokine receptors are transcriptionally distinct, suggesting nonredundant functions for CCR1, CCR2, and CCR5. Finally, we examined changes in macrophage chemokine receptor expression in vitro after treatment with varied Toll-like receptor ligands and show that CCR1 is specifically increased in response to bacterial but not viral ligands. Our data provide compelling evidence that macrophage chemokine receptor expression is not redundant, but rather is specific and malleable in response to discrete inflammatory stimuli.