Research ArticleEDEMA

Macrophage depletion induces edema through release of matrix-degrading proteases and proteoglycan deposition

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Science Translational Medicine  16 Jun 2021:
Vol. 13, Issue 598, eabd4550
DOI: 10.1126/scitranslmed.abd4550

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Elucidating edema formation

Colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising anticancer therapy that depletes macrophages, but treatment is associated with edema. Bissinger et al. studied the changes to the extracellular matrix associated with anti-CSF1R treatment. They found an increase in matrix-modulating proteins and depletion of macrophages in the skin that preceded the deposition of hyaluronan and proteoglycans in mice treated with anti-CSF1R. In patients treated with the CSF1R inhibitor emactuzumab, serum hyaluronan increase was more pronounced in individuals that developed edema. This study helps uncover the mechanisms underlying anti-CSF1R–associated edema formation and suggests that inhibiting matrix-modulating proteins could help combat fluid retention.

Abstract

Colony-stimulating factor 1 receptor (CSF1R) blockade abates tumor-associated macrophage (TAM) infiltrates and provides marked clinical benefits in diffuse-type tenosynovial giant cell tumors. However, facial edema is a common adverse event associated with TAM elimination in patients. In this study, we examined molecular and cellular events associated with edema formation in mice and human patients with cancer treated with a CSF1R blocking antibody. Extended antibody treatment of mice caused marked body weight gain, an indicator of enhanced body fluid retention. This was associated with an increase of extracellular matrix–remodeling metalloproteinases (MMPs), namely MMP2 and MMP3, and enhanced deposition of hyaluronan (HA) and proteoglycans, leading to skin thickening. Discontinuation of anti-CSF1R treatment or blockade of MMP activity restored unaltered body weight and normal skin morphology in the mice. In patients, edema developed at doses well below the established optimal biological dose for emactuzumab, a CSF1R dimerization inhibitor. Patients who developed edema in response to emactuzumab had elevated HA in peripheral blood. Our findings indicate that an early increase of peripheral HA can serve as a pharmacodynamic marker for edema development and suggest potential interventions based on MMP inhibition for relieving periorbital edema in patients treated with CSF1R inhibitors.

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