Syntaxin-2 balances phagocytic uptake and phagolysosomal clearance in macrophages

Phagocytosis engulfs receptor-bound particles within phagosomes that mature into acidic, hydrolase-enriched phagolysosomes for content degradation. Although an essential process for host defense and homeostasis, defective or uncontrolled phagocytosis can be detrimental. We report here, that syntaxin-2 (Stx2), a poorly characterized SNARE in phagocytes, defines the course of macrophage phagocytosis by coordinating surface receptor density, phagosome biogenesis and maturation. Stx2 is expressed primarily on the plasma membrane, early endosomes and phagosomes. Stx2 knockdown (Stx2-KD) increases entrapment and uptake of IgG-opsonized particles owing to dysregulated formation and expansion of phagocytic cups driven by elevated IgG receptor recycling and trafficking of early endosomes and VAMP4-positive post-Golgi compartments to phagocytic cups. Interestingly, Stx2-KD decreases secretion of pro-cathepsins and increases lysosome content. However, Stx2-KD impedes phagosome maturation by preventing coalescence with late endosomes, lysosomes and reducing phagosomal acidification. Consequently, Stx2-depleted macrophages exhibit aberrant uptake of IgG-opsonized bacteria and impaired digestion, resulting in increased intracellular accumulation of intact bacteria. Collectively, Stx2 critically balances phagocytic uptake and phagolysosomal clearance in macrophages, suggesting that Stx2 could be an attractive target to modulate phagocytosis plasticity and to control aberrant phagocytosis.