What molecules are responsible for the early rolling of neutrophils on the endothelium during inflammation?

Selectins Mediate Early Neutrophil Rolling on Endothelium During Inflammation

The early "rolling" of neutrophils on endothelium during inflammation is primarily mediated by selectins (option a). 1, 2, 3

Molecular Mechanisms of Neutrophil-Endothelial Interactions

The recruitment of neutrophils to inflammatory sites follows a well-defined cascade that begins with the initial rolling phase:

1. Initial Rolling Phase (Selectin-Mediated)

   • Activated endothelium expresses P-selectin and E-selectin on its luminal surface 1
   • These selectins interact with carbohydrate ligands on neutrophils, initiating the rolling process 2
   • L-selectin, constitutively expressed on leukocytes, also contributes to this initial rolling interaction 3
   • This selectin-mediated rolling occurs under physiological blood flow conditions and is the first step in neutrophil recruitment 2, 4

2. Firm Adhesion Phase (Integrin-Mediated)

   • After rolling, neutrophils establish firm adhesion through interactions between:
     • Neutrophil integrins (CD11a/CD18 or LFA-1, CD11b/CD18 or Mac-1) 1, 2
     • Endothelial adhesion molecules (ICAM-1, VCAM-1) 1, 5
   • This step follows the selectin-mediated rolling and precedes transmigration 2

3. Transmigration Phase (Multiple Molecules)

   • After firm adhesion, neutrophils migrate through the endothelium (diapedesis) 6
   • This process involves immunoglobulin superfamily members and other adhesion molecules 7

Evidence Supporting Selectins as Mediators of Rolling

• In vitro studies demonstrate that E-selectin expressed on cell surfaces supports neutrophil rolling under flow conditions 4
• Monoclonal antibodies against selectins significantly reduce neutrophil rolling and subsequent inflammation in various models 2, 3
• The selectin family consists of three members with differential expression patterns:
  • L-selectin: expressed on leukocytes 3
  • P-selectin: rapidly mobilized from storage granules to endothelial cell surface upon stimulation 2
  • E-selectin: synthesized by endothelial cells following cytokine stimulation 2

Clinical Significance

• Selectin-mediated rolling is a critical first step in the inflammatory cascade that can lead to tissue damage in various pathological conditions 1
• In sepsis, this process contributes to the conversion of endothelium from an anticoagulant to a procoagulant state 8, 9
• Excessive neutrophil recruitment and activation can contribute to vascular damage and organ dysfunction 8

Distinguishing from Other Adhesion Molecules

• Integrins (option d): Function primarily in firm adhesion after the initial rolling phase, not in the early rolling process 2, 5
• Immunoglobulin superfamily (option c): Includes ICAM-1 and VCAM-1, which are involved in firm adhesion rather than initial rolling 1, 5
• N-cadherins (option b): Not significantly involved in neutrophil-endothelial interactions during inflammation 7
• Complement activation (option e): While complement can enhance inflammation, it does not directly mediate the physical rolling of neutrophils 9

The sequential nature of neutrophil recruitment (rolling → adhesion → transmigration) involves different adhesion molecule families at each step, with selectins uniquely specialized for the initial rolling phase under flow conditions 2, 3.