Discrete functions of M 2a and M 2c macrophage subsets determine their relative efficacy in treating chronic kidney disease

Abstract

Two types of alternatively activated macrophages, M(2a) induced by IL-4/IL-13 and M(2c) 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, M(2c) macrophages more effectively reduced glomerulosclerosis, tubular atrophy, interstitial expansion, and proteinuria than M(2a) macrophages. The M(2c) macrophages were also more effective than M(2a) in reduction of macrophage and CD4(+) T-cell infiltration in kidney. Moreover, nephrotic mice treated with M(2c) had a greater reduction in renal fibrosis than those treated with M(2a). M(2c) but not M(2a) 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 M(2c) was due to their capability to induce Tregs, the Tregs were depleted by PC61 antibody in nephrotic mice treated with M(2a) or M(2c). Treg depletion diminished the superior effects of M(2c) compared to M(2a) in protection against renal injury, inflammatory infiltrates, and renal fibrosis. Thus, M(2c) are more potent than M(2a) macrophages in protecting against renal injury due to their ability to induce Tregs.

Drug delivery strategies to control macrophages for tissue repair and regeneration

“…Lu et al 48 showed that injecting in vitro-polarized murine M2c macrophages (stimulated with IL10 and TGFb) or M2a macrophages (stimulated with IL4 and IL13) to the same chronic inflammatory renal mouse model promoted different protective functions, though both M2a and M2c reduced CD4þ and CD8þ T cell infiltration and tissue inflammation. 48 M2c macrophages recruited regulatory T cells and caused a reduction in glomerulosclerosis, tubular atrophy, interstitial expansion, and proteinuria.…”

“…48 M2c macrophages recruited regulatory T cells and caused a reduction in glomerulosclerosis, tubular atrophy, interstitial expansion, and proteinuria. 48 These findings highlight the important role of M2c macrophages in modulating the immune system and protecting against tissue damage. However, much is still unknown about the role of M2c macrophages in vivo.…”

“…45 Macrophage-treated rats exhibited improved myofibroblast accumulation, vascularization, and scar thickening, which overall prevented infarct expansion and led to better functional outcomes. 45 Local injection of macrophages also has been shown to improve vascularization and healing in bone, 46 ischemic hind limb tissue injury, 47 renal injury, 32,48 and spinal cord injury. 49 These positive outcomes likely result from the secretion of an array of beneficial cytokines and growth factors by macrophages, but future studies should focus on determining the precise mechanisms of action in order to facilitate clinical translation, especially considering there are disadvantages associated with delivering living cells.…”

“…64 The authors attributed this finding to a failure to allow an early inflammatory (M1) phase to occur prior to the administration of the macrophages, as had been done in the aforementioned studies of renal injury. 32,48 Clearly, more research is required to gain a better understanding of the optimal timing for their administration and their therapeutic functions in different tissues.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…These cells exhibit a remarkable phenotypic plasticity and functional overlap. They exert various functions depending on their phenotype and pathological context which can result in proor anti-fibrotic effects or have no effects at all (23,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Apart from a number of chemokines driving their influx and activation such as CX3CR1 (28,30,31,41), several molecules also play an important role including galectin-3 (42,43), the receptor for macrophage colony-stimulating factor (44), the Wnt pathway ligand Wnt7b (45) and interleukin 10 (46).…”