Neutrophil Adhesion and Migration

Neutrophil Adherence to Endothelium

• Stage 1: "rolling" mediated by selectins, newly expressed on the endothelium
• Stage 2: "adhesion" mediated by integrin proteins, constitutively expressed on the endothelium and the neutrophil
• Stage 3: "emigration" also mediated by integrins

Selectins and Integrins

• Selectins: on neutrophils and endothelial cells, mediate rolling
• Integrins: on neutrophils, bind to adhesion molecules on endothelial cells, mediate adhesion and emigration

Leucocyte and Endothelial Cell Interactions

• During inflammation, endothelial cells and leucocytes interact through specific molecular interactions, facilitating the migration of leucocytes from the bloodstream to the site of inflammation.
• Endothelial molecules interacting with leucocyte integrins: ICAM-1 (intercellular adhesion molecule 1), VCAM-1 (vascular cell adhesion molecule 1), MadCAM-1 (mucosal addressin cell adhesion molecule 1)
• Leucocyte integrins: α4β1 (very late antigen-4, VLA-4), α4β7, β2 (complement receptor 3, CR3)
• These interactions are crucial for the firm adhesion and transmigration of leucocytes across the endothelium, a critical step in the inflammatory response.

Neutrophil Movement in Tissues

• Chemotaxis: increased unidirectional movement towards the source of the signal, which is crucial for neutrophils to reach the site of inflammation or infection. This process is mediated by specific receptors on the surface of neutrophils that recognize and respond to chemotactic signals.
• Chemotaxin: agent that can induce chemotaxis in target cells, such as interleukin-8 (IL-8), leukotriene B4 (LTB4), and formyl-methionyl-leucyl-phenylalanine (fMLP). These chemotaxins are secreted by various cell types, including immune cells, endothelial cells, and epithelial cells, and play a key role in guiding neutrophils to the site of infection.

Kinetics of Human Neutrophil Production and Loss

• Produced in the bone marrow at ~1.5 million cells per second
• Spend about 12 hours in blood and up to 24 hours in tissues
• Terminally differentiated cells, cannot proliferate under any circumstances

Neutrophil Events in Acute Inflammation

• Margination in small vessels: This process involves the migration of neutrophils to the margins of blood vessels, where they can adhere to the endothelium and prepare for emigration into the surrounding tissue.
• Emigration from vessel into tissue: Also known as extravasation, this process involves the neutrophils crossing the endothelium and entering the surrounding tissue, where they can respond to inflammatory signals and fight infection.
• Phagocytosis of micro-organisms: Once in the tissue, neutrophils can engulf and digest foreign particles and microorganisms, such as bacteria, using a process called phagocytosis, which helps to eliminate the infection.
• Killing of micro-organisms: Through the release of reactive oxygen species and antimicrobial peptides, neutrophils can actively kill microorganisms, helping to clear the infection.
• Death of neutrophil: After completing their function, neutrophils undergo programmed cell death, or apoptosis, which helps to prevent excessive inflammation and tissue damage.
• Tissue accumulation of leukocytes in inflammation: The accumulation of leukocytes, including neutrophils, in the tissue is a hallmark of inflammation and is essential for the elimination of pathogens and the initiation of the healing process.

Phagocytosis

• Formation of the phagosome
• Involves recognition, engulfment, and phagosome formation
• Phagocytosis ensures generation of reactive oxygen species into the phagosome

Phagocytosis: Formation of the Phagolysosome

• Granules fuse with phagosome
• Phagolysosome formation

Neutrophil Extracellular Traps (NETs)

• Released by dying neutrophils
• Made up of DNA strands with anti-microbial proteins attached
• Trap and kill bacteria

Formation of Neutrophil Extracellular Traps

• Granule proteins adhere to DNA strands
• Neutrophil lyses, NETs released