[Research Articles] Macrophage depletion induces edema through release of matrix-degrading proteases and proteoglycan deposition

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.

Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Bissinger, S., Hage, C., Wagner, V., Maser, I.-P., Brand, V., Schmittnaegel, M., Jegg, A.-M., Cannarile, M., Watson, C., Klaman, I., Rieder, N., Gonzalez Loyola, A., Petrova, T. V., Cassier, P. A., Gomez-Roca, C., Sibaud, V., De Palma, M., Hoves, S., Ries Tags: Research Articles Source Type: research