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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 other extreme, M2 anti-inflammatory cells have a reparative phenotype and can contribute to the resolution 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 end-stage renal disease, and the CD206+ subset of M2 macrophages is strongly associated with renal 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.

Key points

  • Macrophages 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 renal 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.

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Fig. 1: Phenotype and function of bone-marrow-derived monocytes and macrophages in the injured kidney.
Fig. 2: Induction of M1 macrophages in renal inflammation.
Fig. 3: Regulation of the macrophage-to-myofibroblast transition.
Fig. 4: Duration of TGFβ1 signalling determines macrophage phenotype in renal repair and fibrosis.
Fig. 5: Potential therapeutic targets in macrophage-mediated renal injury.

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Acknowledgements

The authors’ work is supported by grants from the Lui Che Woo Institute of Innovative Medicine (CARE programme), the Research Grants Council of Hong Kong (GRF 14106518, 14117418, 14117815, 14121816, 14163317, C7018-16G and TRS T12-402/13 N), the Health and Medical Research Fund (03140486 and 14152321), the Major State Basic Research Development Program of China (2012CB517705), a Direct Grant for Research from the Chinese University of Hong Kong (2017.002) and the National Health and Medical Research Council of Australia (1122073).

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Nature Reviews Nephrology thanks S. Ricardo, B. Conway and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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P.M.-K.T. and D.J.N.-P. drafted the manuscript. H.-Y.L. and D.J.N.-P. supervised the design, writing and content of the manuscript. All authors reviewed and/or edited the final version of the manuscript and agree to be accountable for all aspects of the work.

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Correspondence to Hui-Yao Lan.

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Glossary

Clodronate liposomes

Phospholipid bilayers (that is, liposomes) that encapsulate the cytotoxic drug clodronate; these liposomes are used for the depletion of phagocytic cells as they are selectively taken up by phagocytes and cause cell death.

Fibrocytes

A population of immature myeloid cells in the bone marrow that differentiate into CD45+type I collagen+ fibroblast-like cells that are released into the circulation and can promote wound repair and tissue fibrosis.

Tumour-associated macrophages

A subset of macrophages in the tumour microenvironment that inhibit immune cell-mediated destruction of tumour cells and promote tumour growth via stimulation of angiogenesis.

Asiatic acid

A triterpenoid component extracted from Centella asiatica, which has anti-inflammatory and antifibrotic actions, including the increase in Smad7 expression.

Naringenin

A flavonoid from grapefruit and citrus fruits that has anti-inflammatory properties, including inhibition of Smad3 function.

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Tang, P.MK., Nikolic-Paterson, D.J. & Lan, HY. Macrophages: versatile players in renal inflammation and fibrosis. Nat Rev Nephrol 15, 144–158 (2019). https://doi.org/10.1038/s41581-019-0110-2

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