Discrete functions of M2a and M2c macrophage subsets determine their relative efficacy in treating chronic kidney disease

Two types of alternatively activated macrophages, M2a induced by IL-4/IL-13 and M2c by IL-10/TGF-β, exhibit anti-inflammatory functions in vitro and protect against renal injury in vivo. Since their relative therapeutic efficacy is unclear, we compared the effects of these two macrophage subsets in murine adriamycin nephrosis. Both subsets significantly reduced renal inflammation and renal injury; however, M2c macrophages more effectively reduced glomerulosclerosis, tubular atrophy, interstitial expansion, and proteinuria than M2a macrophages. The M2c macrophages were also more effective than M2a in reduction of macrophage and CD4+ T-cell infiltration in kidney. Moreover, nephrotic mice treated with M2c had a greater reduction in renal fibrosis than those treated with M2a. M2c but not M2a macrophages induced regulatory T cells (Tregs) from CD4+CD25- T cells in vitro, and increased Treg numbers in local draining lymph nodes of nephrotic mice. To determine whether the greater protection with M2c was due to their capability to induce Tregs, the Tregs were depleted by PC61 antibody in nephrotic mice treated with M2a or M2c. Treg depletion diminished the superior effects of M2c compared to M2a in protection against renal injury, inflammatory infiltrates, and renal fibrosis. Thus, M2c are more potent than M2a macrophages in protecting against renal injury due to their ability to induce Tregs.