IL-17A induced hematopoietic reprogramming produces both PMN and MDSC at the post-acute stage of inflammation.

Abstract

Our previous study suggests that polymorphonuclear leukocyte (PMN) response is enhanced at the post-acute stage of murine colitis due to changes in bone marrow (BM) myelopoiesis. Herein, we report that hematopoietic reprogramming during the post-acute phase of inflammation produces myeloid derived suppressor cells (MDSC) that co-infiltrate the intestine with PMN. Employing Percoll density gradients, we analyzed dynamic changes to the myeloid compartment by separating BM leukocytes from DSS colitis-to-recovery mice into four density-increasing bands with myeloid leukocytes enriched in bands III (50–60%) and IV (60–70%). Band III was comprised of monocytes and low-density granulocytes; both confirmed to be M-MDSCs and G-MDSCs, respectively, by displaying potent inhibition of T-cell proliferation. Despite significant decreases in the PMN population, presumably caused by mobilization into inflamed tissues, MDSC numbers significantly increase beginning at the post-acute stage of colitis. Furthermore, MDSC numbers do not return to baseline until late in the recovery stage. The expanded G-MDSCs also showed increased CXCR2 expression, which guides egress out of BM, and produced ROS upon PMA activation. Adoptive transfer assays demonstrated that functionally enhanced PMN infiltrated the intestine at the post-acute stage to clear the existing inflammatory reaction, while MDSC accumulated in the intestine during recovery suggesting a role in tissue repair. IL-17A signaling at the post-acute stage of inflammation likely induced hematopoietic reprogramming of the myeloid compartment, as its neutralization blocked expansion and infiltration of both PMN and MDSC.