The ‘core’ structure of podosomes is primarily composed of branched F-actin nucleated by the Arp2/3 complex. Interestingly, podosomes are mechanosensitive ( Labernadie et al., 2014 van den Dries et al., 2019b), generating greater forces in response to stiffer substrates, and thus podosome-like structures may contribute to the mechanosensitivity observed in phagocytosis, whereby phagocytes engulf stiffer targets more readily than softer ones ( Beningo and Wang, 2002 Jaumouillé et al., 2019 Sosale et al., 2015 Vorselen et al., 2020b Vorselen et al., 2020a). Podosomes are specialized F-actin adhesive structures that are prominent in myeloid cells and capable of generating forces and degrading extracellular matrix ( Linder, 2007 van den Dries et al., 2019a). This suggests a fundamentally different mechanism for cup shaping based on assembly of individual actin-based protrusions versus a uniform actin meshwork. Yet recent studies have identified dynamic adhesions or podosome-like structures within the phagocytic cup that appear to be sites of actin polymerization ( Barger et al., 2019 Ostrowski et al., 2019). Previously, F-actin within the phagocytic cup was generally considered to be homogenous and the membrane extensions around the target were frequently likened to lamellipodia at the leading edge of a migrating cell ( Blanchoin et al., 2014 Davidson and Wood, 2020 Jaumouillé and Waterman, 2020 Small et al., 2002). Mechanically, progression of the phagocytic cup is powered by F-actin polymerization that pushes the plasma membrane forward and culminates in the eventual closure of the cup and the formation of a membrane-enclosed phagosome ( Vorselen et al., 2020a). Selective engagement and specific exclusion of phagocyte receptors ( Freeman et al., 2018 Freeman et al., 2016) enables downstream signaling to initiate the formation of membrane protrusions, which are guided around the target through sequential ligand engagement in a zipper-like fashion to form the phagocytic cup ( Griffin and Silverstein, 1974 Jaumouillé and Waterman, 2020 Swanson and Hoppe, 2004). Phagocytosis is initiated when phagocytic receptors recognize distinct molecular patterns coating the target ( Freeman and Grinstein, 2014 Uribe-Querol and Rosales, 2020). Given the variety of phagocytic targets, ranging widely in shape, size, and mechanical stiffness, this process requires remarkable plasticity. Phagocytic uptake of microbial pathogens, apoptotic cells, and debris are essential processes for human health ( Boada-Romero et al., 2020 Lim et al., 2017). Overall, our findings present a phagocytic cup shaping mechanism that is distinct from cytoskeletal remodeling in 2D cell motility and may contribute to mechanosensing and phagocytic plasticity. Observations of partial target eating attempts and sudden target release via a popping mechanism suggest that constriction may be critical for resolving complex in vivo target encounters. Contractile myosin-II activity contributes to late-stage phagocytic force generation and progression, supporting a specific role in phagocytic cup closure. This constriction is largely driven by Arp2/3-mediated assembly of discrete actin protrusions containing myosin 1e and 1f (‘teeth’) that appear to be interconnected in a ring-like organization. We show that spatially localized forces leading to target constriction are prominent during phagocytosis of antibody-opsonized targets. Here, we combine lattice light-sheet microscopy (LLSM) with microparticle traction force microscopy (MP-TFM) to quantify actin dynamics and subcellular forces during macrophage phagocytosis. How actomyosin activity directs membrane extensions to engulf such diverse targets remains unclear. Phagocytosis requires rapid actin reorganization and spatially controlled force generation to ingest targets ranging from pathogens to apoptotic cells.
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