Macrophages in Kidney Repair and Regeneration
Authors: Jeremy S. Duffield
Journal: Journal of the American Society of Nephrology (2011)

Appreciation of a central role for recruited monocyte-derived macrophages to repair organs after injury is gaining considerable momentum. In the past 2 years, monocyte-derived tissue leukocytes have been identified as orchestrators of repair in skin, muscle, gut, brain, and heart. Macrophages, however, exhibit considerable plasticity in their phenotype and can polarize into functional states that additionally contribute to tissue injury or fibrosis. These functional states have become known as M1 for pro-injurious functions and M2 for wound-healing functions, but this nomenclature belies the complexity of macrophage diversity. The phenotypic switch that is central to macrophage-directed repair and the effectors of this repair merit further study. In kidney diseases, monocyte-derived tissue effector cells, known as macrophages, have a bad reputation along with neutrophils as drivers of tissue injury and fibrosis.1 Although this is certainly true and therapies that target injurious macrophages and injurious mechanisms of the innate immune system that wreak havoc inappropriately in our organs are greatly welcomed, it seems that proinflammatory macrophages and neutrophils are the exception that proves the rule.1,2. What is the rule? The innate immune system serves to police our organs and promote repair and regeneration without causing injury. Only in overwhelming circumstances such as infection or severe tissue injury do macrophages activate sterilizing and injurious programs. Macrophages are particularly adept at clearing debris, extracellular matrix, immune complexes, and dead cell products of tissue injury and most of the time perform such tasks silently.3 The same sort of macrophages also seem to have the capacity to release almost every cytokine and growth factor described in the literature. Coordinated release of many of these factors promotes organized tissue regeneration including basement membrane synthesis, cell proliferation, cell migration, and dampening of the inflammatory response. In some circles, reparative monocyte-derived cells with avidity for microvascular repair are known as endothelial progenitor cells (EPCs). EPCs are now widely described to promote capillary repair and restoration by a number of mechanisms, including canalization of new capillary tracts, temporary (days to weeks) replacement of endothelial cells in areas of denuded capillary basement membrane, new capillary basement membrane synthesis, cytokine release that promotes endothelial cell proliferation, and adoption of pericyte functions.4,5 But can the endogenous reparative functions of macrophages be harnessed for good in the kidney? It seems so. Lee et al.2 in this issue of JASN set out to test whether deliberate manipulation of inflammatory monocyte/macrophages alters the course of injury and repair in kidney ischemia reperfusion injury (IRI). In loss-of-function studies, the authors specifically ablate monocytes and macrophages using a toxic drug encapsulated within liposomes. Ablation at the onset of injury was protective, whereas ablation during the repair phase was deleterious. In gain-of-function studies, they adoptively transferred into the circulation macrophages that were recruited to the injured kidney. Macrophages primed with IFN-γ to adopt an M1 or injurious phenotype exacerbated injury, but adoptively transferred macrophages primed to exhibit a wound-healing phenotype lacked this capacity. Typical macrophage M1 markers such as nitric oxide synthase 2 were found in early kidney injury, whereas typical macrophage M2 markers such as the mannose receptor were detected during the repair phase. When the investigators adoptively transferred M1-primed macrophages to the kidney early after injury and then tracked them, they noted the transferred cells activated the M2 markers, the mannose receptor, and Arginase with time, indicative of a phenotypic switch. M2-primed macrophages had a specific capacity to stimulate tubular cell proliferation in vitro and in vivo. Thus, during the normal repair of kidney injured by ischemia, macrophages acquire regenerative functions, which included stimulating successful epithelial proliferation. These findings are entirely consistent with several other studies published in the past year in which macrophages or the monocyte-derived dendritic cells were ablated during the repair phase of IRI in the kidney with deleterious outcomes.6–8 These other studies used a genetic system to ablate macrophages, which has significant methodologic differences compared with the report from Lee et al.2 Nevertheless, the consistent message is that macrophages promote normal repair and regeneration after injury, and a major component of that process is stimulation of epithelial regeneration by cell–cell cross-talk. In none of these studies or the study by Lee et al.,2 however, has the role of macrophages in repair of the capillaries of regenerating kidney been studied, yet the parallels between monocyte-derived EPCs in microvascular repair and macrophages in epithelial repair are striking, and vital peritubular capillaries are severely disrupted in ischemic kidney injury.9 In models of single toxic, ischemic, or surgical injury of heart, skeletal muscle, gut, pancreas, liver, brain, and skin, a wave of repairing monocyte-derived cells moves into the tissue and orchestrates a repair and regeneration program.4,10–14 This suggests the observations in kidney repair reflect a generalized function of the macrophage, one that can be harnessed for therapeutic benefit. What next? Although we now know that macrophages can promote repair, the studies of Lee et al.2 tell us this occurs at the expense of M1 activation followed by a phenotypic switch and that M1-activated macrophages can be deleterious. With the advent of cell therapy, it may be possible to administer primed monocytes to the circulation that do not require M1 activation to deliver regenerative functions to the kidney. Studies of this nature (IL-10–expressing adoptively transferred macrophages) were performed nearly 10 years ago in the laboratory of David Kluth and Andy Rees in rat models of glomerulonephritis, but, although convincing, this line of investigation never made it to human studies.15 Perhaps we should revisit this as a therapeutic strategy. It is clear that while in the experimental tissue milieu of post-IRI kidney macrophages cause repair in rodents, this environment may not often be present in human disease, and many studies of rodents show that macrophages in chronic renal injury actually drive injury and fibrosis.1 Understanding which tissue factors trigger a phenotypic switch toward tissue repair and regeneration and the macrophage effectors that bring about repair and regeneration may bear more therapeutic fruit for humans in need of macrophage-directed therapy in the future. To that end, several studies now implicate successful delivery of the macrophage cytokine IL-10 to the kidney or stimulation of macrophage Wnt signaling pathways in epithelium as potential therapeutic options for human disease.6,16 DISCLOSURES None. The Laboratory of Inflammation Research is supported by National Institutes of Health grants DK73299, DK84077, and DK87389; University of Washington; Genzyme GRIP award; and an award from Regulus Inc.