Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury

Abstract

Interstitial fibrosis is an important contributor to graft loss in chronic renal allograft injury. Inflammatory macrophages are associated with fibrosis in renal allografts, but how these cells contribute to this damaging response is not clearly understood. Here, we investigated the role of macrophage-to-myofibroblast transition in interstitial fibrosis in human and experimental chronic renal allograft injury. In biopsy specimens from patients with active chronic allograft rejection, we identified cells undergoing macrophage-to-myofibroblast transition by the coexpression of macrophage (CD68) and myofibroblast (-smooth muscle actin [-SMA]) markers. CD68/-SMA cells accounted for approximately 50% of the myofibroblast population, and the number of these cells correlated with allograft function and the severity of interstitial fibrosis. Similarly, in C57BL/6J mice with a BALB/c renal allograft, cells coexpressing macrophage markers (CD68 or F4/80) and -SMA composed a significant population in the interstitium of allografts undergoing chronic rejection. Fate-mapping in Lyz2-Cre/Rosa26-Tomato mice showed that approximately half of-SMA myofibroblasts in renal allografts originated from recipient bone marrow-derived macrophages. Knockout of protected against interstitial fibrosis in renal allografts and substantially reduced the number of macrophage-to-myofibroblast transition cells. Furthermore, the majority of macrophage-to-myofibroblast transition cells in human and experimental renal allograft rejection coexpressed the M2-type macrophage marker CD206, and this expression was considerably reduced in-knockout recipients. In conclusion, our studies indicate that macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. Moreover, the transition of bone marrow-derived M2-type macrophages to myofibroblasts in the renal allograft is regulated a Smad3-dependent mechanism.

Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model

“…Mechanistically, M2 cells can produce growth factors such as TGF-β and PDGF, which are crucial mediators of vascular changes by inducing smooth muscle cell proliferation, activation of myofibroblasts and extracellular matrix deposition (32, 33). Moreover, a recent report indicates that α-SMA + myofibroblasts contributes to interstitial fibrosis in chronic renal allograft injury, and approximately 50% of these myofibroblasts are derived from M2 macrophages (34). All these studies suggest the significance of M2 macrophages in mediating chronic allograft rejection.…”

“…32,33 Moreover, a recent report indicates that α-smooth muscle actin positive myofibroblasts contribute to interstitial fibrosis in chronic renal allograft injury, and that approximately 50% of these myofibroblasts are derived from M2 macrophages. 34 All these studies suggest the significance of M2 macrophages in mediating chronic allograft rejection. In the present study we found that mTOR deletion in macrophages inhibited M2 polarization in vitro, thereby decreased the expression of M2 marker genes in graft-infiltrating macrophages, and prevented the development of transplant vasculopathy following CTLA4-Ig treatment.…”

Early interstitial macrophage infiltration with mild dysfunction is associated with subsequent kidney graft loss

“…6 This finding is in keeping with a possible role of macrophages in promoting the activation and recruitment of myofibroblasts to areas of inflammation and eventually leading to fibrosis 11 and is consistent with a recent paper reporting that the macrophage-to-myofibroblast transition may contribute to interstitial fibrosis in both human and experimental chronic allograft injury. 12 Moreover, macrophage infiltration is also associated with poor long-term eGFR behavior in kidneys from deceased but not from living donors, thus confirming a potential role of early inflammation in the risk of subsequent CKD in KTRs after transplantation, and somewhat explaining the better outcome observed in KTRs receiving kidneys from living donors. 13 Another important finding of our study is that in our patients early and severe macrophage infiltration proved to be even more predictive of subsequent graft loss than early IFTA, which characterizes chronic kidney allograft dysfunction and usually develops before any significant clinical evidence of graft damage appears.…”

Inhibition of microRNA-376b Protects Against Renal Interstitial Fibrosis via Inducing Macrophage Autophagy by Upregulating Atg5 in Mice with Chronic Kidney Disease

“…Renal interstitial fibrosis (RIF) is a common pathway leading to the progressive loss of kidney function in CKD [7]. Accumulating studies have illustrated that macrophages play a role in RIF, and we thus speculate that macrophage autophagy can prevent RIF [8][9][10]. Understanding the molecular signaling mechanisms underlying the involvement of macrophage autophagy in RIF will lead to novel treatments of CKD.…”