Macrophages: versatile players in renal inflammation and fibrosis

Abstract

Macrophages have important roles in immune surveillance and in the maintenance of kidney homeostasis; their response to renal injury varies enormously depending on the nature and duration of the insult. Macrophages can adopt a variety of phenotypes: at one extreme, M1 pro-inflammatory cells contribute to infection clearance but can also promote renal injury; at the\xa0other extreme, M2 anti-inflammatory cells have a reparative phenotype and can contribute to\xa0the\xa0resolution phase of the response to injury. In addition, bone marrow monocytes can differentiate into myeloid-derived suppressor cells that can regulate T cell immunity in the kidney. However, macrophages can also promote renal fibrosis, a major driver of progression to\xa0end-stage renal disease, and the CD206+ subset of M2 macrophages is strongly associated with\xa0renal fibrosis in both human and experimental diseases. Myofibroblasts are important contributors to renal fibrosis and recent studies provide evidence that macrophages recruited from the bone marrow can transition directly into myofibroblasts within the injured kidney. This process is termed macrophage-to-myofibroblast transition (MMT) and is driven by transforming growth factor-β1 (TGFβ1)–Smad3 signalling via a Src-centric regulatory network. MMT may serve as a key checkpoint for the progression of chronic inflammation into pathogenic fibrosis.Macrophages are versatile immune cells that protect the host against infection but can also promote chronic inflammation and fibrosis. In this Review, the authors discuss the diverse roles of macrophages in acute and chronic renal pathology as well as potential therapeutic targets.Key pointsMacrophages have important roles in kidney homeostasis and in the response to acute and chronic kidney injury.Macrophage phenotype varies enormously depending on the nature and duration of\xa0renal injury, ranging from the pro-inflammatory phenotype of M1 cells to the anti-inflammatory phenotype of M2 cells that are involved in tissue repair and fibrosis; monocytic myeloid-derived suppressor cells contribute to immune regulation.Macrophages are plastic cells and their gene expression patterns and functions adapt rapidly to the dynamics of the renal microenvironment.CD206+ M2 macrophages are strongly associated with renal fibrosis in human and experimental kidney diseases.Macrophages derived from bone marrow cells can directly contribute to renal fibrosis through a process termed macrophage-to-myofibroblast transition (MMT).The induction of MMT, via the Src-centric regulatory network mediated by transforming growth factor-β1 (TGFβ1)–Smad3, serves as a key checkpoint in the progression of chronic inflammation to renal fibrosis.