Colony-Stimulating Factor-1 Promotes Kidney Growth and Repair via Alteration of Macrophage Responses

Abstract

Colony-stimulating factor (CSF)-1 controls the survival, proliferation, and differentiation of macrophages, which are recognized as scavengers and agents of the innate and the acquired immune systems. Because of their plasticity, macrophages are endowed with many other essential roles during development and tissue homeostasis. We present evidence that CSF-1 plays an important trophic role in postnatal organ growth and kidney repair. Notably, the injection of CSF-1 postnatally enhanced kidney weight and volume and was associated with increased numbers of tissue macrophages. Moreover, CSF-1 promotes postnatal renal repair in mice after ischemia-reperfusion injury by recruiting and influencing macrophages toward a reparative state. CSF-1 treatment rapidly accelerated renal repair with tubular epithelial cell replacement, attenuation of interstitial fibrosis, and functional recovery. Analysis of macrophages from CSF-1-treated kidneys showed increased expression of insulin-like growth factor-1 and anti-inflammatory genes that are known CSF-1 targets. Taken together, these data suggest that CSF-1 is important in kidney growth and the promotion of endogenous repair and resolution of inflammatory injury.

Macrophages and CSF-1

“…23 Indeed, these F4/80 bright yolk sac-derived macrophages displayed the characteristic spindle-shape morphology in close association with the developing kidney and lung epithelium as described previously. 13,60 Furthermore, through pulse labeling of CSF-1R + yolk sac-derived macrophages at E8, they demonstrated that at 4 weeks of age the resident populations within these organs contains macrophages derived from this early yolk sac lineage. 23 While there is a capacity for bone marrow-derived replacement of cells in settings of depletion and injury, it remains of interest whether resident populations are maintained through in situ proliferation.…”

“…91,132 We have previously reported that the systemic supplementation of postnatal CSF-1 in mice promoted an increase in overall organ growth and body weight, that may be due in part to increased expression of IGF-1. 13 This raises new information regarding the potential mechanism of trophic macrophage function in organogenesis and also supports an emerging link between CSF-1, macrophages and the IGF-1 growth axis. 133 Growth hormone (GH) and IGF-1 interact to provide the principle regulatory mechanism of somatic growth in mammals.…”

“…[7][8][9][10][11] In particular it is the influence of CSF-1 in regulating an alternative macrophage activation state that is increasingly linked to organ repair in a range of disease models. [12][13][14][15][16][17] With many similarities drawn between organogenesis and regeneration, it is pertinent to re-examine the role of CSF-1 and macrophages in organ development.…”

Polarization of Macrophages in Metabolic Diseases

“…In addition to CNS migration, these mononuclear phagocytes also populate the kidney where they mature into kidney resident monocytes [19]. These kidney resident monocytes expand during chronic kidney disease and produce a unique cytokine signature, compared to the inflammation attracted monocytes and function mainly to provide signals regulating organ growth and repair during physiological stress [20,21]. However, aberrant activity of these kidney resident cells has been considered to participate in the extensive fibrotic activity present in chronic metabolic disorders.…”

Renal organogenesis

“…In this model, you do get a massive amount of tubular death, a lot of macrophage infiltration during the obstruction phase, and then you do see a lot of tubular turnover, and we see a lot of changes in the Crim1 profile. Based on a study that I haven't shown you, 56 we think there is a switch in the behavior of the interstitial macrophages from an inflammatory to a reparative state, and hence, you get really strong support of the tubular epithelium to recover. However, if you have gone past the "point of no return" in any nephron, you don't get a new nephron.…”