Biochemical and biophysical mechanisms macrophages use to tune phagocytic appetite

Abstract

Macrophages phagocytose, or eat, pathogens, dead cells and cancer cells. To activate phagocytosis, macrophages recognize 'eat me' signals like IgG and phosphatidylserine on the target cell surface. Macrophages must carefully adjust their phagocytic appetite to ignore non-specific or transient eat me signal exposure on healthy cells while still rapidly recognizing pathogens and debris. Depending on the context, macrophages can increase their appetite for phagocytosis, to prioritize an effective immune response, or decrease their appetite, to avoid damage to healthy tissue during homeostasis. In this Review, we discuss the biochemical and biophysical mechanisms that macrophages employ to increase or decrease their sensitivity or capacity for phagocytosis. We discuss evidence that macrophages tune their sensitivity via several mechanisms, including altering the balance of activating and inhibitory receptor expression, altering the availability of activating receptors, as well as influencing their clustering and mobility, and modulating inhibitory receptor location. We also highlight how membrane availability limits the capacity of macrophages for phagocytosis and discuss potential mechanisms to promote membrane recycling and increase phagocytic capacity. Overall, this Review highlights recent work detailing the molecular toolkit that macrophages use to alter their appetite.

Keywords: ADCP; Efferocytosis; IgG; Macrophage; Phagocytic Appetite; Phagocytosis.

Fig. 1.

Macrophage appetite is dependent on sensitivity and capacity. Macrophage appetite varies along two parameters – sensitivity and capacity. Mechanisms that change sensitivity affect the ability of the macrophage to sense and respond to phagocytosis-activating ‘eat me’ signals on their targets. For instance, changing receptor availability or binding avidity can shift the macrophage response curve left or right. Mechanisms that change phagocytic capacity affect the ability of macrophage to engulf and process multiple targets and can shift the top of the curve up or down. Created in BioRender by Morrissey, M., 2024. https://BioRender.com/l38j896. This figure was sublicensed under CC-BY 4.0 terms.

Fig. 2.

The balance of activating versus inhibitory signaling controls macrophage phagocytosis. (A) More signaling from activating receptors compared to inhibitory receptors leads to phagocytosis. (B) More signaling from inhibitory receptors compared to activating receptors inhibits phagocytosis. Created in BioRender by Morrissey, M., 2024. https://BioRender.com/s22m770. This figure was sublicensed under CC-BY 4.0 terms.

Fig. 3.

Phagocytic receptor availability can be modulated through multiple mechanisms. Receptor availability can be modulated by (A) transcriptional changes affecting receptor expression levels, (B) receptor internalization, which reduces available ligand-binding sites, (C) ectodomain shedding, which can cause sequestration of ligands away from signaling domains, (D) post-translational modifications, such as conformational changes that affect ligand binding affinities, and (E) glycosylation that can affect receptor or ligand accessibility. Created in BioRender by Morrissey, M., 2024. https://BioRender.com/k90q464. This figure was sublicensed under CC-BY 4.0 terms.

Fig. 4.

Receptor clustering modulates phagocytosis. (A) Clustering of activating receptors (such as FcγRs and Draper) amplifies phagocytic signals. (B) Co-clustering of different activating receptors (such as co-clustering of FcγRs with Toll-like receptors) can lead to synergy that increases phagocytosis. (C) Inhibitory receptor signaling is more potent when receptors are co-clustered with activating phagocytic receptors, as is the case with co-clustering of SIRPA and FcγRs. Created in BioRender by Morrissey, M., 2024. https://BioRender.com/g68s525. This figure was sublicensed under CC-BY 4.0 terms.

Fig. 5.

Mechanisms macrophages use to restore plasma membrane abundance during phagocytosis. Membrane abundance, a key limiting factor of phagocytic appetite, can be regulated through (A) increased membrane biogenesis and (B) target digestion and membrane recycling, both of which can each supply additional membrane to newly forming phagocytic cups. ROS, reactive oxygen species. Created in BioRender by Morrissey, M., 2024. https://BioRender.com/n66q510. This figure was sublicensed under CC-BY 4.0 terms.