RBP-J regulates homeostasis and function of circulating Ly6C^lo monocytes.

Abstract

Notch-RBP-J signaling plays an essential role in the maintenance of myeloid homeostasis. However, its role in monocyte cell fate decisions is not fully understood. Here, we showed that conditional deletion of transcription factor RBP-J in myeloid cells resulted in marked accumulation of blood Ly6C^lo monocytes that highly expressed chemokine receptor CCR2. Bone marrow transplantation and parabiosis experiments revealed a cell-intrinsic requirement of RBP-J for controlling blood Ly6C^loCCR2^hi monocytes. RBP-J-deficient Ly6C^lo monocytes exhibited enhanced capacity competing with wildtype counterparts in blood circulation. In accordance with alterations of circulating monocytes, RBP-J deficiency led to markedly increased population of lung tissues with Ly6C^lo monocytes and CD16.2⁺ interstitial macrophages. Furthermore, RBP-J deficiency-associated phenotypes could be genetically corrected by further deleting <i>Ccr2</i> in myeloid cells. These results demonstrate that RBP-J functions as a crucial regulator of blood Ly6C^lo monocytes and thus derived lung-resident myeloid populations, at least in part through regulation of CCR2.