Downregulation of the atypical chemokine receptor ACKR2 expression by hematopoietic progenitors promotes myeloid cell mobilization and differeniation

The atypical receptor ACKR2 is a scavenger receptor for many inflammatory CC chemokines and it has been shown to prevent the development of exacerbated inflammatory reactions. ACKR2 is expressed either by non-hematopoietic cell compartment or by hematopoietic cells. The aim of this investigation was to gain inside into the role of ACKR2 in myeloid cells trafficking and differentiation. To address the role of ACKR2 in the proposed research we took advantage from ACKR2-gene targeted mice, FACS analysis, primary cell cultures and cell line. Monocytes and neutrophils from ACKR2-/- mice had increased chemokine-induced mobilization and pharmacological blocking experiments revealed that it was CXCR4-independent. ACKR2-/- mice showed increased number of monocytes confined to bone marrow sinusoids compared to wild type. Bone marrow chimera experiments showed that the increased mobilization was due to the hematopoietic compartment. The analysis of hematopoietic progenitors revealed that ACKR2 is expressed by Lin−Sca-1+c-Kit+ cells (LSK) to faint thereafter in more mature myeloid progenitors in contrast with canonical chemokine receptor CCR2. Moreover myeloid committed progenitors from ACKR2-/- mice expressed high levels of CCR1, CCR2 and CCR5, but not of CXCR4 and they had higher proliferation and differentiation rate compared to ACKR2 sufficient LSK. These data suggest that ACKR2 is not only involved in regulating chemokine gradient and leukocytes recruitment, but can directly regulate cell activity through the inhibition of chemokine receptor expression by a mechanism still unclear. Collectively these results demonstrate that ACKR2 is differentially expressed by hematopoietic progenitors during myeloid cell maturation and its expression on LSK is involved in controlling their localization and mobilization.