The Diverse Function of Macrophages in Renal Disease

This presentation was given by Jeremy Hughes from the University of Edinburgh. It was presented at the ISN’s Forefronts Symposium 2015 taking place in Shenzhen, China, on October 22-25, 2015 for which the theme was ‘Immunomodulation of Cardio-Renal Function’ during Session 2: Innate and Adaptive Immunity and Renal Pathology.

View the Presentation:

Presentation Abstract: 

Macrophages are multifunctional innate immune cells. Increased macrophage infiltration is a feature of acute inflammatory and chronic fibrotic kidney disease in humans whilst macrophages are also involved in renal regeneration. Experimental macrophage depletion limits renal injury and scarring and impairs renal regeneration. Macrophages play a role in glomerulonephritis, diabetic nephropathy, tubulointerstitial fibrosis, acute kidney injury, transplant rejection, cystic disease and renal preconditioning thus reinforcing their importance across a spectrum of renal pathology.

During disease states macrophages may adopt various activation phenotypes that may be pro-inflammatory, pro-fibrotic or reparative. Indeed, macrophages may transit between such phenotypes within renal tissue such as following renal ischaemia reperfusion injury (IRI). Although macrophage phenotype is commonly discussed in the context of the ‘M1/M2 macrophage’ paradigm, it should be appreciated that the phenotypes adopted by these cells are more diverse and subtle as they are generated in response to multiple microenvironmental cues that evolve and change during disease.
Chemokines and growth factors such as colony stimulating factor-1 (CSF-1) promote macrophage accumulation and proliferation within the injured or diseased kidney whilst cytokines, growth factors and apoptotic cell ingestion can modulate macrophage polarization. Mitogen driven macrophage proliferation in situ may provide an opportunity for the generated daughter cells to reassess the nature of the microenvironment and adopt an appropriate phenotype. In addition, CSF-1 acts to limit pro-inflammatory macrophage activation and promote a wound healing phenotype via the upregulation of microRNA-21 expression. Macrophages are highly receptive to signals derived from the renal parenchyma and the interaction of pro-inflammatory macrophages with tubular epithelial cells can result in the down-regulation of macrophage activation. Recent work in a model of renal IRI indicates that granulocyte macrophage colony stimulating factor (GM-CSF) derived from tubular epithelial cells drives macrophages to adopt a reparative phenotype that actively promotes tubular proliferation. These studies highlight the key role of the tissue parenchyma in directing macrophage polarization to facilitate subsequent repair but, although this may facilitate the resolution of acute injury, it may be less successful during chronic disease.

Aging may modulate the function of macrophages as well as other immune cells and the reduced upregulation of the anti-inflammatory enzyme hemeoxygenase-1 by renal macrophages in aged mice is associated with more severe acute kidney injury following renal IRI. The pharmacological induction of macrophage hemeoxygenase-1 expression in aged mice prior to renal IRI confers marked protection and we are exploring this approach in patients aiming to prevent or limit acute kidney injury. The administration or macrophages of a known phenotype has been used as ‘cell therapy’ in several experimental models. A macrophage ‘trojan horse’ strategy can be used to deliver a specific anti-inflammatory molecule or simply macrophages that have been programmed -ex vivo to adopt an anti-inflammatory phenotype and this approach can ameliorate experimental disease.
It is envisaged that a deeper understanding of the induction and control of macrophage activation phenotype, the intracellular signaling pathways that regulate macrophage responses and the mediators involved in the cross-talk between macrophages and parenchymal cells will lead to novel therapeutic approaches for patients with kidney disease.