Macrophages are sentinel cells of the body, one of whose main functions is phagocytosis, i.e. the uptake and degradation of large particles such as microorganisms and cellular debris. This process depends on actin polymerization, which drives plasma membrane deformation around the target particle. The influence of the microenvironment, and especially its mechanical properties, on the ability of macrophages to perform phagocytosis remains to be completely understood. In addition, the effect of phagocytosis on the way macrophages interact with their environment is not well known.
To understand the influence of the mechanical properties of a tissue on phagocytosis, the authors of this study first analysed the effect of substrate stiffness on macrophages’ phagocytic capacities. The cells were cultured on polyacrylamide gels of varying stiffnesses, which cover the physiological range of stiffnesses found in the body, and the authors showed that the number of internalized particles as well as actin recruitment during phagocytosis were modulated by substrate stiffness.
Live traction microscopy experiments to monitor the forces exerted by macrophages on their substrate during phagocytosis demonstrated that phagocytosing macrophages interacted more dynamically with their surroundings. The authors also showed that phagocytosis led to a transient disruption of adhesion structures that macrophages form at the interface with their substrate, called podosomes, concomitantly with actin accumulation at the phagocytic cup. This was associated with decreased degradation of the extracellular matrix, which is characteristic of podosomes.
Figure: Summary of the results obtained in this study. Substrate stiffness modulates CR3-mediated phagocytic uptake in macrophages (1). CR3-mediated phagocytosis leads to an active remodeling of macrophage adhesion, with a transient disassembly of podosomes that is concomitant with F-actin recruitment at the phagocytic cup and decreased substrate degradation (2). In addition, phagocytosing macrophages interact more dynamically with their substrate.
These results highlight the existence of a crosstalk between adhesion and phagocytosis in macrophages, contributing to the better understanding of how the microenvironment shapes cell responses and vice-versa. This represents a major challenge for pathologies where macrophages participate in disease progression and particularly for those characterized by altered tissue mechanics, such as fibrosis and cancer.
Reference
Depierre M, Mularski A, Ruppel A, Le Clainche C, Balland M and Niedergang F. A crosstalk between adhesion and phagocytosis integrates macrophage functions into their microenvironment. iScience 2025. https://doi.org/10.1016/j.isci.2025.112067
