Margination

• Definition: a process by which leukocytes are distributed peripherally along the endothelial surface
• Mechanism: The two main mechanisms that allow for margination are rouleaux formation and dilation of post-capillary venules.

Rolling

• Definition: a transient weak interaction of leukocytes with endothelial cells that causes them to move slowly along the blood vessel periphery in areas of inflammation in preparation for adhesion
• Mechanism: mediated by adhesion molecules (selectins)
  • On endothelial cells
    • P-selectin
      • Stored in Weibel-Palade bodies
      • Histamine-mediated release within the endothelium in response to inflammation
    • E-selectin: released in response to inflammatory mediators such as TNF and IL-1
    • Other: GlyCAM-1, CD34
  • On leukocytes
    • Neutrophils and other leukocytes express Sialyl-LewisX and L-selectin, respectively.
    • Deficiency of the adhesion molecule Sialyl-LewisX causes Leukocyte adhesion deficiency type 1 type 2.

Leukocyte adhesion

• Definition: the firm binding of leukocytes to endothelium prior to migrating out of the vasculature
• Mechanism: mediated by adhesion molecules
  • On endothelial cells
    • Intercellular adhesion molecule (ICAM, also called CD54)
    • Vascular adhesion molecule (VCAM, also called CD106)
    • Both upregulated by TNF and IL-1
  • On neutrophils and lymphocytes
    • Neutrophils: lymphocyte function-associated antigen-1 (LFA-1)
      • Belongs to β2-integrin family
      • Composed of CD18 and CD11a
      • Binds to ICAM
    • Lymphocytes and monocytes β1-integrin (also called VLA-4) binds to VCAM
    • Expression of integrins is activated by leukotriene B4 (LTB4) and C5a.
    • The deficiency of a CD18 integrin subunit causes Leukocyte adhesion deficiency type 1.

Tip

Selectins are molecules that allow leukocytes to select the place of their migration (weak binding), while integrins are molecules that integrate (strong binding) the leukocytes with the endothelial cells.

Diapedesis (transmigration)

• Definition: the transmigration of leukocytes across endothelial barriers (can occur paracellularly or transcellularly)
• Mechanism
  • Leukocytes leave the blood vessel by moving between endothelial cells.
  • Neutrophils release type IV collagenase, which dissolves the basement membrane and allows them to exit the interstitial space.
  • Requires expression of platelet endothelial cell adhesion molecule-1 (PECAM-1, also called CD31), an endothelial cell adhesion molecule (ECAM) on neutrophils, endothelial cells, and platelets

Migration

• Definition: the process by which leukocytes travel through the interstitium to the site of inflammation after leaving the blood vessels
• Mechanism: Occurs via chemotaxis, which is mediated by chemoattractants
  • Leukotrienes: e.g., LTB4
  • Platelet-activating factor (PAF)
  • Chemokines: e.g., IL-8
  • Kallikrein: a serine protease enzyme that activates bradykinin and regulates blood pressure
  • Complement fragments, e.g., C5a