Phagocytosis Stages

• Phagocytes are vital for innate immunity.
• They ingest microbes, remove debris, and connect innate and adaptive immune responses.
• Phagocytosis is crucial in inflammation, involving the ingestion of microbes and removal of cellular debris, presenting their components to immune cells.
• A macrophage ingests bacteria using pseudopodia to entrap and internalize them.

Stages of Phagocytosis

• Chemotaxis: Phagocytes move towards infection sites, attracted by chemoattractants from microbes or damaged cells.

  • Neutrophils and macrophages have receptors to detect these signals.

• Recognition and Attachment: Phagocytes recognize foreign particles via receptors interacting with pathogen-associated molecular patterns (PAMPs).

  • Toll-like receptors (TLRs) on phagocytes bind to PAMPs.

• Engulfment: Phagocytes extend pseudopods to enclose the particle in a phagosome.

  • The cytoskeleton reorganizes to facilitate this process.

• Phagosome Formation: The particle is enclosed in a membrane-bound vesicle, separating it from the cytoplasm.

• Phagosome Maturation: The phagosome fuses with endosomes and lysosomes, forming a phagolysosome.

  • Lysosomes contribute digestive enzymes, creating an acidic environment.

• Digestion and Killing: Enzymes degrade the particle, and reactive oxygen species (ROS) kill pathogens.

  • Lysosomal enzymes such as proteases and lipases break down the particle.

• Exocytosis: Residual material is expelled from the phagocyte.

  • The phagolysosome membrane fuses with the cell membrane to release remnants.

• Microbes, once internalized, are contained in a phagosome that merges with a lysosome to create a phagolysosome.

• Phagolysosomes employ various mechanisms to kill and digest microbes.

• Phagocytes digest microbes using lysosomal acid hydrolysis, oxygen radicals, superoxide radicals, hydrogen peroxide, and hydroxyl radicals.

• This process is known as oxidative burst and occurs within the phagolysosome.

• Increased nitrous oxide levels and decreased pH assist in digesting microbes.

Mechanisms of Intracellular Killing

• Recognition and Phagocytosis: Phagocytic cells use pattern recognition receptors (PRRs) to recognize and engulf pathogens via pathogen-associated molecular patterns (PAMPs).

• Phagosome Formation: The engulfed pathogen is enclosed within a phagosome.

• Formation of the Phagolysosome: Phagosomes fuse with lysosomes, creating a phagolysosome containing antimicrobial substances.

• Respiratory Burst (Oxidative Burst): Rapid increase in oxygen consumption and production of reactive oxygen species (ROS) within the phagolysosome.

• Activation of NADPH Oxidase: NADPH oxidase is activated and moves to the phagosome membrane.

• Production of Superoxide Anion (O2·-): NADPH oxidase generates superoxide anion by transferring electrons from NADPH to oxygen.

• Formation of Reactive Oxygen Species (ROS): Superoxide anion leads to the formation of other ROS, like hydrogen peroxide (H2O2) and hydroxyl radicals (OH·).

• Antimicrobial Activity: ROS damage proteins, lipids, and nucleic acids, aiding in pathogen destruction.

• Activation of Other Antimicrobial Mechanisms: Antimicrobial substances like peptides and lysozyme are released, enhancing killing.

• Resolution of Inflammation: Anti-inflammatory signals resolve inflammation and prevent tissue damage after pathogens are neutralized.

• Effective Microbial Killing: ROS effectively kill microorganisms.

• Contribution to Immune Defense: Oxidative burst is essential for innate immunity.

• Link to Immunodeficiencies: Deficiencies in NADPH oxidase can lead to immunodeficiencies like chronic granulomatous disease (CGD).

• During oxidative burst, the cell uses oxygen to produce toxic oxygen metabolites targeting microbes

• NADPH oxidase reduces oxygen to form superoxide anion (O2-), damaging microbial DNA and proteins.

• Myeloperoxidase catalyzes the reaction between hydrogen peroxide and chloride ions to produces hypochlorite, effectively killing microbes.

• Inducible nitric oxide synthase (iNOS) converts arginine into nitric oxide (NO), which is toxic to microbes.

• Nitric oxide combines with superoxide to form peroxynitrite (ONOO-), a damaging molecule.

• Lysozyme breaks down peptidoglycan in bacterial cell walls, causing them to burst

• Defensins are antimicrobial peptides that create holes in microbial membranes, leading to lysis and death

• Macrophages and neutrophils patrol the body, ingesting debris, bacteria, and dead cells.

• A strep attaches to macrophage receptors, which extends pseudopods.

• The strep is engulfed by the cell membrane, forming a phagosome.

• An electron pump lowers the pH inside the phagosome.

• The phagosome fuses with a lysosome, forming a phagolysosome containing digestive enzymes.

• Lysosomal enzymes in the phagolysosome destroy the bacteria with the help of an acidic pH.

• The macrophage expels the leftovers into the extracellular space.