An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation

Abstract

The development of the mononuclear phagocyte system requires macrophage colony-stimulating factor (CSF-1) signaling through the CSF-1 receptor (CSF1R, CD115). We examined the effect of an antibody against CSF1R on macrophage homeostasis and function using the MacGreen transgenic mouse (csf1r-enhanced green fluorescent protein) as a reporter. The administration of a novel CSF1R blocking antibody selectively reduced the CD115 ؉ Gr-1 neg monocyte precursor of resident tissue macrophages. CD115 ؉ Gr-1 ؉ inflammatory monocytes were correspondingly increased, supporting the view that monocytes are a developmental series. Within tissue, the antibody almost completely depleted resident macrophage populations in the peritoneum, gastrointestinal tract, liver, kidney, and skin, but not in the lung or female reproductive organs. CSF1R blockade reduced the numbers of tumor-associated macrophages in syngeneic tumor models, suggesting that these cells are resident type macrophages. Conversely, it had no effect on inflammatory monocyte recruitment in models, including lipopolysaccharide-induced lung inflammation, wound healing, peritonitis, and severe acute graft-versus-host disease. Depletion of resident tissue macrophages from bone marrow transplantation recipients actually resulted in accelerated pathology and exaggerated donor T-cell activation. The data indicate that CSF1R signaling is required only for the maturation and replacement of resident-type monocytes and tissue macrophages, and is not required for monocyte production or inflammatory function. (Blood.

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

“…We have recently reported that the administration of CSF-1R blocking antibody selectively reduced monocyte precursors of resident tissue macrophages. 67 The current study suggests that CSF-1 acts, at least in part, through production of IGF-1 by kidney macrophages. We further propose that an activation of CSF-1 by tissue macrophages creates a microenvironment that influences the growth, proliferation, and differentiation of renal epithelial cells and promotes matrix remodeling and Figure 9.…”

Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice

“…A recent study, however, reported that the number of circulating monocytes was not reduced in M-CSF-deficient mice (6). Consistently, Ab blocking of CSF1R in mice selectively inhibited monocyte maturation in the periphery without affecting their numbers (30). Despite these discrepancies, current evidence suggests that M-CSF is likely involved in the maturation and survival rather than the production of monocytes in mice.…”

Intestinal macrophages – specialised adaptation to a unique environment

“…Like most tissue Mjs, these cells are dependent upon CSF-1 [11] and are absent in mice lacking CD115 (CSF-1R) [46]. According to the current dogma, these resident Mjs should derive from Ly6C low monocytes [47], but adoptive transfer experiments show that Ly6C high monocytes can give rise to both CX3CR1 low/int (''inflammatory'') and CX3CR1 high (''resident'') MPs in the 'steady-state' intestine (Fig.…”