Macropinocytosis: New Insights Into Its Underappreciated Role in Innate Immune Cell Surveillance

Abstract

Macropinocytosis has received increasing attention in recent years for its various roles in nutrient acquisition, immune surveillance, and virus and cancer pathologies. In most cases macropinocytosis is initiated by the sudden increase in an external stimulus such as a growth factor. This "induced" form of macropinocytosis has been the subject of much of the work addressing its mechanism and function over the years. An alternative, "constitutive" form of macropinocytosis restricted to primary innate immune cells also exists, although its mechanism has remained severely understudied. This mini-review focuses on the very recent advances that have shed new light on the initiation, formation and functional relevance of constitutive macropinocytosis in primary innate immune cells. An emphasis is placed on how this new understanding of constitutive macropinocytosis is helping to define the sentinel function of innate immune cells including polarized macrophages and dendritic cells.

Keywords: Nod2 signaling adaptor protein; PRRs; antigen presentation; dendritic cells; macrophages; macropinocytosis; macropinosome; pattern recognition receptors (PRRs).

Figure 1

Constitutive macropinocytosis is initiated by the sensing of extracellular calcium by the G protein-coupled receptor CaSR. CaSR ligation initiates a signaling cascade ultimately resulting in the elaboration of an Arp2/3 dependent branched actin network at the plasma membrane that drives constitutive ruffling. Early macropinosomes are less acidic due to limited contact with late endosomes/lysosomes and likely NADPH oxidase activity. The generation of reactive oxygen species damages the integrity of the macropinosome membrane through lipid peroxidation thus allowing for the release of antigen into the cytosol necessary for subsequent cross-presentation. As the macropinosome matures, the lumen becomes increasingly acidic allowing for the activation of protease and lipases with acidic pH optima. This degradative environment facilitates the generation of peptides that can bind MHCII for presentation. Similarly, the degradative environment can liberate NOD1/2 ligands that can be transported in a pH-dependent manner across the macropinosomal membrane into the cytosol where they can bind cytosolic PRRs. Luminal ligands for membrane bound PRRs such as TLR4, TLR7 and TLR9 can also bind their respective receptors once internalized.