Macrophages Regulate Renal Fibrosis Through Modulating TGFβ Superfamily Signaling

Abstract

Renal fibrosis is the fundamental pathway leading to end-stage renal disease, while its exact molecular basis remains incompletely elucidated. Previous studies have demonstrated that transforming growth factor beta 1 (TGFβ1) is an inducer of the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells, while bone morphogenic protein 7 (BMP7) counteracts TGFβ1-induced EMT and reverses chronic renal injury. Although macrophage recruitment is believed to play an important role during the whole pathogenesis, the mechanism underlying their activate involvement in the formation of renal fibrosis besides phagocytosizing extracellular matrix and apoptotic cells is largely unknown. Here, in a mouse unilateral ureteral obstruction (UUO) model, we show that the recruited macrophages are mainly M1 macrophages at early stage. However, these F4/80-positive and CD301-negative M1 macrophages were shortly polarized into F4/80-positive and CD301-positive M2 macrophages, respectively, which released high levels TGFβ1, to contradict the local expression of BMP7 to facilitate EMT-induced renal fibrosis. M2 macrophages depletion specifically inhibited EMT, and subsequently the renal fibrosis. Adoptive transplantation of M2 macrophages increased the features of renal fibrosis. Our study thus identified double-edged effects of macrophages in the formation of renal fibrosis, which suggest that modulation of macrophage polarization may substantially improve the treatment of renal fibrosis.

Regulation of Renal Fibrosis by Macrophage Polarization

“…TGFβ1 induces renal tubular epithelial cell EMT, while BMP7 counteracts TGFβ1-induced EMT [12,14,30]. Moreover, the macrophages are known to play essential roles in the development of renal fibrosis, but the present concerns on macrophages were mostly limited to their roles as phagocytes to clean tissue debris [10,18,31]. …”

Mesenchymal Stem Cells Recruit Macrophages to Alleviate Experimental Colitis Through TGFβ1

“…Macrophages are a type of white blood cell that is responsible for phagocytosis in the body. Besides the macrophages with classical phenotype, called “M1” macrophages, another macrophage sub-type, called “M2”, is often associated with neovascularization, fibrosis and tissue repair [12,14,15,16,17,18,19,20,21,22]. The conversion between M1 and M2 characteristics for macrophages is called “polarization”.…”

“…The conversion between M1 and M2 characteristics for macrophages is called “polarization”. Specifically, M2 macrophages are known to secrete a wide range of chemokines, enzymes and growth factors, among which TGFβ1 is a critical one [12,19,20]. Recent studies have shown that MSCs may not only recruit macrophages, but also induce their polarization into a M2 phenotype, in different organs, and in different models [12,14,19,20].…”

“…Specifically, M2 macrophages are known to secrete a wide range of chemokines, enzymes and growth factors, among which TGFβ1 is a critical one [12,19,20]. Recent studies have shown that MSCs may not only recruit macrophages, but also induce their polarization into a M2 phenotype, in different organs, and in different models [12,14,19,20]. Although we did examine the M1/M2 polarization of macrophages in the current study, it is highly possible that the functional macrophages here are M2, due to high TGFβ1 levels in macrophages, and due to the dependence on TGFβ1 in the MSCs-induced alleviation of the DSS-colitis.…”

Mesenchymal Stem Cells Mitigate Cirrhosis through BMP7

“…Major regulators of EMT in the liver are two multifunctional growth factors from transforming growth factor β (TGFβ) superfamily [18,19,20], bone morphogenic protein 7 (BMP7) and TGFβ1. While TGFβ1 is a well-established fibrotic inducer to promote transdifferentiation of hepatic stellate cells into myofibroblasts, BMP7 reverses EMT by directly counteracting TGFβ1-induced Smad-dependent cell signaling [21,22,23,24,25]. Such antagonism coordinates the repair of the injured liver [26,27,28,29,30].…”