# CCL5 paradoxically regulates glomerular injury by skewing macrophage polarization

## TL;DR

CCL5 protects kidney cells in the lab but worsens kidney disease by promoting harmful immune cells from bone marrow, suggesting therapies should target specific cell types.

## Contribution

CCL5's paradoxical role in kidney disease is revealed, showing it protects podocytes in vitro but exacerbates injury in vivo via macrophage polarization.

## Key findings

- CCL5 protects cultured podocytes by reducing apoptosis and promoting survival.
- CCL5 in bone marrow-derived cells worsens glomerular injury by promoting M1 macrophages and inhibiting M2 differentiation.
- CCL5 deficiency in bone marrow-derived cells reduces kidney damage and increases reparative M2 macrophages.

## Abstract

Glomerular inflammation and podocyte loss are the hallmarks of chronic kidney disease (CKD) progression. Understanding how podocytes and their microenvironment regulate inflammation is critical for developing effective therapies. In this study, we identified C-C chemokine ligand 5 (CCL5) as an inflammatory mediator elevated in injured podocytes, based on analyses of both human kidney biopsies and mouse models of CKD. We discovered that CCL5 exerts paradoxical effects in nephropathy; while it protects podocytes in vitro, it exacerbates glomerular injury in vivo. Recombinant CCL5 and podocyte-specific CCL5 overexpression promoted cell survival and reduced apoptosis in cultured podocytes. However, in adriamycin-induced nephropathy, CCL5 worsened glomerular injury, increasing proteinuria, glomerulosclerosis, and podocyte loss. Bone marrow (BM) transplantation experiments revealed that CCL5 in BM-derived cells — not kidney-resident cells — drove disease progression. CCL5 deficiency in BM-derived cells conferred protection by increasing reparative M2 macrophages, whereas endogenous CCL5 promoted M1 polarization, inhibited M2 differentiation, and triggered M2-to-M1 transition. These findings demonstrate that while CCL5 supports podocyte survival, its expression in BM-derived cells promotes inflammatory macrophage phenotypes and glomerular injury. The harmful immune effects of CCL5 in BM-derived cells outweigh its podocyte-protective role, highlighting the importance of cell-targeted strategies to mitigate kidney damage.

CCL5 protects kidney-filtering podocytes but worsens nephropathy by driving inflammatory macrophages from bone marrow, highlighting the need for cell-specific therapies in kidney disease.