Bone marrow-derived Ly6C^- macrophages promote ischemia-induced chronic kidney disease

Macrophages play an important role in renal injury and repair after acute kidney injury (AKI) and the subsequent chronic kidney disease (CKD) that often results. However, as macrophages have a high degree of plasticity and heterogeneity, the function(s) of macrophage subtypes in AKI-to-CKD progression are not fully understood. Here, we focused on Ly6C^- macrophages, which are derived from the embryonic yolk sac and post-development become resident in the kidneys. We found that C-C chemokine receptor type 2 (CCR2) deficiency, which blocks the migration of Ly6C⁺ macrophages from the bone marrow to the sites of injury, alleviated ischemia-induced AKI in mice. Unexpectedly, though, CCR2 deficiency worsened the subsequent renal fibrosis, which was marked by notable intra-renal infiltration of Ly6C^- macrophages. These Ly6C^- macrophages were greater in number in both the acute and chronic phases after ischemia reperfusion (I/R) in kidneys of wild type (WT) mice, and we showed them to be derived from the bone marrow by bone marrow chimerism. Clodronate Liposomes (CLs)-mediated depletion of renal Ly6C^- macrophages in CCR2^-/- mice or in WT mice after I/R alleviated the renal injury and fibrosis. On the contrary, adoptive transfer of Ly6C^- macrophages from injured kidneys of WT mice into immune-deficient mice was sufficient to induce renal injury and fibrosis. Transcriptome sequencing of Ly6C^- macrophages from injured kidneys revealed that they secreted various cytokines and growth factors, which were associated with the transdifferentiation of fibroblasts into myofibroblasts. This transdifferentiation effect was further supported by in vitro studies showing that Ly6C^- macrophages induced the secretion of extracellular matrix proteins from co-cultured fibroblasts. In conclusion, the presence of bone marrow-derived Ly6C^- macrophages after ischemia induces AKI and worsens subsequent CKD.