Mice lacking two or all three selectins demonstrate overlapping and distinct functions for each selectin.

Area of Science:

• Immunology
• Cellular Biology
• Inflammation Research

Background:

• Selectins (L-, E-, P-) are crucial for leukocyte capture and rolling in inflammation and homing.
• Single selectin deficiencies cause mild to moderate defects in inflammatory cell recruitment.
• Combined P- and E-selectin deficiency leads to severe neutrophilia and reduced lifespan.

Purpose of the Study:

• To investigate the roles of combined selectin deficiencies (L/P-/-, L/E-/-, E/L/P-/-) in leukocyte recruitment.
• To determine the necessity of each selectin in supporting neutrophil recruitment.

Main Methods:

• Generation of novel triple and double selectin knockout mice (L/P-/-, L/E-/-, E/L/P-/-) using bone marrow transplantation.
• Assessment of leukocyte rolling and adhesion in response to trauma and TNF-alpha-induced inflammation.
• Inhibition studies using anti-alpha4 integrin antibodies in triple knockout mice.

Main Results:

• L/P-/- mice (E-selectin only) exhibited absent rolling after trauma and ~90% reduced rolling after TNF-alpha.
• L/E-/- mice (P-selectin only) showed rolling velocities similar to L-/- mice.
• E/L/P-/- mice displayed minimal rolling, completely blocked by anti-alpha4 integrin, with significantly reduced neutrophil adhesion and emigration at 6h post-TNF-alpha.

Conclusions:

• Each selectin can independently support some level of neutrophil recruitment.
• Complete absence of all three selectins significantly impairs neutrophil recruitment.
• Selectins play a critical, albeit partially redundant, role in inflammatory leukocyte trafficking.