Leukocyte migration to the inflammation site

Adhesion molecules: who slows the cells down

For a cell to stop and exit the bloodstream, it needs adhesion molecules. The main condition for their function is contact reversibility. Of the four groups of molecules in mammals, three are critical for myeloid cells: selectins, integrins, and members of the immunoglobulin superfamily (IgSF).

Selectins are tissue lectins that bind terminal carbohydrate residues (mannose and fucose) strictly in the presence of $Ca^{2+}$ ions.

• L-selectins are constitutively expressed on leukocytes.
• E-selectins appear on the endothelium only after its activation by cytokines.
• P-selectins are stored in endothelial and platelet granules, rapidly moving to the surface upon alarm.

Vascular endothelial activation

Migration is initiated by resident macrophages at the lesion site. Upon encountering a pathogen, they release cytokines (primarily IL-1β and TNFα).

Endothelial cells of postcapillary venules have constant receptors for these mediators and react instantly:

1. Change shape from flat to tall.
2. Express adhesion molecules: P- and E-selectins, addressins (receptors for L-selectins), and integrins (ICAM-1, VCAM-1).
3. Begin actively secreting pro-inflammatory cytokines and chemokines themselves.

Four stages of transvascular migration

The interaction of leukocytes with the prepared endothelium proceeds in four stages:

1. Rolling. Lasts 1–5 seconds. The leukocyte's L-selectins weakly and reversibly bind to endothelial ligands (e.g., Gly-CAM). Blood flow breaks these bonds, causing the cell to "roll" along the wall.
2. Activation. Takes up to 20 seconds. Endothelial chemokines (e.g., IL-8) act on leukocyte receptors. With the participation of Rho family proteins, a signal is generated that "unfolds" inactive integrin molecules (e.g., LFA-1), sharply increasing their affinity for receptors.
3. Firm adhesion. Lasts several minutes. The leukocyte's activated integrin LFA-1 binds firmly to the endothelial molecule ICAM-1. The cell comes to a complete stop.
4. Extravasation (transmigration). Takes up to 10 minutes. The cell squeezes through the vascular wall along a chemoattractant gradient (fMLP, C3a, C5a peptides). Homotypic ("like with like") interactions via CD31 (PeCAM) and CD99 molecules play a crucial role.

Leukocyte progression in tissues

Having left the vessel, the leukocyte orients itself along the gradient of chemotactic factors. For directed movement, the concentration drop must be at least 1% over a distance equal to the cell diameter.

Movement is provided by cytoskeleton remodeling. The cell changes shape from round to triangular. Microtubules set the orientation, and filamentous F-actin contracts, forming an extended forward lamellipodia (a region of cytoplasm poor in organelles). To break through tissue barriers and basement membranes, the leukocyte secretes enzymes: elastase, collagenase, and cathepsins.

Class and exam questions

What else to study on this topic

• Structure of selectins: lectin domain and complement control domains
• Addressins (PNAd) and lymphocyte homing mechanisms
• Chemokine specificity: α-chemokines for neutrophils and β-chemokines for monocytes
• Intracellular signal transduction: the role of Rho family GTP-binding proteins

Other topics in the "Innate Immunity" section

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.