Integrin activation by P-Rex1 is required for selectin-mediated slow leukocyte rolling and intravascular crawling.

Abstract

Integrin activation is essential for the function of leukocytes. Impaired integrin activation on leukocytes is the hallmark of the leukocyte adhesion deficiency syndrome in humans, characterized by impaired leukocyte recruitment and recurrent infections. In inflammation, leukocytes collect different signals during the contact with the microvasculature, which activate signaling pathways leading to integrin activation and leukocyte recruitment. We report the role of P-Rex1, a Rac-specific guanine nucleotide exchanging factor, in integrin activation and leukocyte recruitment. We find that P-Rex1 is required for inducing selectin-mediated lymphocyte function-associated antigen-1 (LFA-1) extension that corresponds to intermediate affinity and induces slow leukocyte rolling, whereas P-Rex1 is not involved in the induction of the high-affinity conformation of LFA-1 obligatory for leukocyte arrest. Furthermore, we demonstrate that P-Rex1 is involved in Mac-1-dependent intravascular crawling. In vivo, both LFA-1-dependent slow rolling and Mac-1-dependent crawling are defective in P-Rex1(-/-) leukocytes, whereas chemokine-induced arrest and postadhesion strengthening remain intact in P-Rex1-deficient leukocytes. Rac1 is involved in E-selectin-mediated slow rolling and crawling. In vivo, in an ischemia-reperfusion-induced model of acute kidney injury, abolished selectin-mediated integrin activation contributed to decreased neutrophil recruitment and reduced kidney damage in P-Rex1-deficient mice. We conclude that P-Rex1 serves distinct functions in LFA-1 and Mac-1 activation.

• Authors: Jan M Herter, Jan Rossaint, Helena Block, Heidi Welch, Alexander Zarbock
• Journal: Blood (Blood) Vol. 121 Issue 12 Pg. 2301-10 (Mar 21 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23343834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• E-Selectin
• Guanine Nucleotide Exchange Factors
• Integrins
• Lymphocyte Function-Associated Antigen-1
• Macrophage-1 Antigen
• PREX1 protein, mouse
• Intercellular Adhesion Molecule-1

Topics

• Acute Kidney Injury (etiology, genetics, pathology)
• Animals
• Blood Vessels (immunology, metabolism, pathology)
• Cells, Cultured
• Chemotaxis, Leukocyte (drug effects, genetics)
• E-Selectin (pharmacology)
• Guanine Nucleotide Exchange Factors (genetics, metabolism, physiology)
• HL-60 Cells
• Humans
• Integrins (metabolism)
• Intercellular Adhesion Molecule-1 (pharmacology)
• Leukocyte Rolling (drug effects, genetics)
• Leukocytes (drug effects, metabolism, physiology)
• Lymphocyte Function-Associated Antigen-1 (genetics, metabolism, physiology)
• Macrophage-1 Antigen (genetics, metabolism, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neutrophil Infiltration (drug effects, genetics)
• Reperfusion Injury (complications, genetics, pathology)