E-Cadherin/β-catenin complex plays an important role in maintaining epithelial integrity and disrupting this complex affect not only the adhesive repertoire of a cell, but also the Wnt-signaling pathway. Aberrant expression of the complex is associated with a wide variety of human malignancies and disorders of fibrosis resulting from epithelial-mesenchymal transition. These associations provide insights into the complexity that is likely responsible for the fibrosis/tumor suppressive action of E-cadherin/β-catenin.

IL-10/TGF-␤-modified macrophages, a subset of activated macrophages, produce anti-inflammatory cytokines, suggesting that they may protect against inflammation-mediated injury. Here, macrophages modified ex vivo by IL-10/TGF-␤ (IL-10/TGF-␤ ⌴2) significantly attenuated renal inflammation, structural injury, and functional decline in murine adriamycin nephrosis (AN). These cells deactivated effector macrophages and inhibited CD4 ϩ T cell proliferation. IL-10/TGF-␤ ⌴2 expressed high levels of the regulatory co-stimulatory molecule B7-H4, induced regulatory T cells from CD4 cells in vitro,and increased the number of regulatory T cells in lymph nodes draining the kidneys in AN. The phenotype of IL-10/TGF-␤ ⌴2 did not switch to that of effector macrophages in the inflamed kidney, and these cells did not promote fibrosis. Taken together, these data demonstrate that IL-10/TGF-␤-modified macrophages effectively protect against renal injury in AN and may become part of a therapeutic strategy for chronic inflammatory disease.

Epithelial-mesenchymal transition (EMT) plays an important role in organ fibrosis , including that of the kidney. Loss of E-cadherin expression is a hallmark of EMT; however , whether the loss of E-cadherin is a consequence or a cause of EMT remains unknown , especially in the renal system. In this study , we show that transforming growth factor (TGF)-␤1-induced EMT in renal tubular epithelial cells is dependent on proteolysis. Matrix metalloproteinase-mediated E-cadherin disruption led directly to tubular epithelial cell EMT via Slug. TGF-␤1 induced the proteolytic shedding of E-cadherin, which caused the nuclear translocation of ␤-catenin , the transcriptional induction of Slug , and the repression of E-cadherin transcription in tubular epithelial cells. These findings reveal a direct role for E-cadherin and for matrix metalloproteinases in causing EMT downstream of TGF-␤1 in fibrotic disease. Specific inhibition rather than activation of matrix metalloproteinases may offer a novel approach for treatment of fibrotic disease. (Am J Pathol

BackgroundMacrophages have heterogeneous phenotypes and complex functions within both innate and adaptive immune responses. To date, most experimental studies have been performed on macrophages derived from bone marrow, spleen and peritoneum. However, differences among macrophages from these particular sources remain unclear. In this study, the features of murine macrophages from bone marrow, spleen and peritoneum were compared.ResultsWe found that peritoneal macrophages (PMs) appear to be more mature than bone marrow derived macrophages (BMs) and splenic macrophages (SPMs) based on their morphology and surface molecular characteristics. BMs showed the strongest capacity for both proliferation and phagocytosis among the three populations of macrophage. Under resting conditions, SPMs maintained high levels of pro-inflammatory cytokines expression (IL-6, IL-12 and TNF-α), whereas BMs produced high levels of suppressive cytokines (IL-10 and TGF-β). However, SPMs activated with LPS not only maintained higher levels of (IL-6, IL-12 and TNF-α) than BMs or PMs, but also maintained higher levels of IL-10 and TGF-β.ConclusionsOur results show that BMs, SPMs and PMs are distinct populations with different biological functions, providing clues to guide their further experimental or therapeutic use.

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.

No abstract

Matrix metalloproteinases (MMPs) are members of the neutral proteinase family. They were previously thought to be anti-fibrotic because of their ability to degrade and remodel of extracellular matrix. However, recent studies have shown that MMPs are implicated in initiation and progression of kidney fibrosis through tubular cell epithelial-mesenchymal transition (EMT) as well as activation of resident fibroblasts, endothelial-mesenchymal transition (EndoMT) and pericyte-myofibroblast transdifferentiation.

Alternatively activated macrophages (M2) regulate immune responses and ex vivo polarized splenic M2 are able to ameliorate renal injury including models of renal disease, such as adriamycin nephropathy. Whether M2 derived from other organs have similar protective efficacy is unknown. Here, we report adoptively transferred bone marrow M2 macrophages did not improve renal function or reduce renal injury in adriamycin nephropathy, whereas splenic M2 macrophages were protective. Bone marrow and splenic M2 macrophages showed similar regulatory phenotypes and suppressive functions in vitro. Within the inflamed kidney, suppressive phenotypes in bone marrow but not in splenic M2 macrophages, were dramatically reduced. Loss of the suppressive phenotype in bone marrow M2 was related to strong proliferation of bone marrow M2. Bone marrow M2 proliferation in vivo correlated with M-CSF expression by tubular cells in the inflamed kidney. Inhibition of M-CSF in vitro limited bone marrow M2 proliferation and prevented switch of phenotype. Proliferating cells derived from transfused bone marrow M2 were inflammatory rather than regulatory in their phenotype and function. Thus bone marrow in contrast to splenic M2 macrophages do not protect against renal structural and functional injury in murine adriamycin nephropathy. The failed renoprotection of bone marrow M2 is due to the switch of transfused M2 macrophages from a regulatory to an inflammatory phenotype.