Microparticle Uptake Reduces Efferocytic Capacity of Macrophages

Abstract

Macrophages are phagocytic immune cells that play a central role in clearance of apoptotic cells, pathogens and other foreign bodies including particulates that may be injected for therapeutic purposes. Recent work has demonstrated that macrophages that take up microparticles clear pathogens faster, however, the effect of particle uptake on clearance of apoptotic cells (efferocytosis) remains unclear. Herein, we use cargo-free, non-stimulatory polymeric particles as a tool to investigate how the uptake of such particles affects the efferocytic function of macrophages. Using primary cells isolated from mice, we demonstrate that uptake of large ~3 µm sized microparticles, but not smaller 500 nm sized particles, reduces a macrophage’s efferocytic ability in vitro. Notably, this effect is pronounced in non-activated M0-type macrophages and absent in activated M1- and M2-type macrophages, highlighting a polarization-dependent resilience towards particulate stress. Given that efferocytosis contributes to an immunosuppressive tumor microenvironment (TME), we leveraged the phenomenon of microparticle uptake driven lowering of efferocytosis to target apoptotic cell clearance in the TME. In a BALB/C mouse model bearing 4T1 tumors, we demonstrate that direct injection of large microparticles into the tumors results in slower tumor growth. Collectively, these findings reveal that cargo-free, non-stimulatory polymeric microparticles of a specific size impact the efferocytic function of macrophages, which may be utilized to alter the TME for therapeutic purposes.