Submitted April 24, 2008
Accepted September 5, 2008
An L-selectin ligand distinct from P-selectin glycoprotein ligand-1 is expressed on endothelial cells and promotes neutrophil rolling in inflammation
Akiko Shigeta, Masanori Matsumoto, Thomas F. Tedder, John B. Lowe, Masayuki Miyasaka, and Takako Hirata*
Laboratory of Combined Research on Microbiology and Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Department of Immunology, Duke University Medical Center, Durham, NC, United States
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
Laboratory of Immunodynamics, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
* Corresponding author; email: thirata{at}biken.osaka-u.ac.jp.
Neutrophils recruited from the blood are key players in the innate immune response. Selectins play critical roles in neutrophil recruitment by mediating their tethering and rolling in inflamed venules. While the roles of P- and E-selectin in this process are well established, the mechanisms of L-selectin-mediated neutrophil recruitment remain elusive. One proposal is that tethering is mediated by L-selectin on flowing neutrophils interacting with P-selectin glycoprotein ligand-1 (PSGL-1) on adherent neutrophils. To clarify whether L-selectin-mediated neutrophil recruitment depends entirely on PSGL-1, we examined the impact of L-selectin deficiency in mice with a PSGL-1-deficient background. L-selectin and PSGL-1 double-knockout mice exhibited a higher increase in their peripheral blood neutrophil count and a worse defect in neutrophil recruitment into the inflamed peritoneum than PSGL-1-deficient mice. Intravital microscopy of inflamed cremaster muscle venules showed that L-selectin deficiency or antibody blockade of L-selectin reduced the residual leukocyte rolling in PSGL-1-deficient mice. Flow cytometric analyses showed that the endothelial cells from the cremaster muscle bound L-selectin in a PSGL-1-independent manner. These results provide evidence for the existence of an L-selectin ligand distinct from PSGL-1 in inflammation, and indicate that such a ligand is expressed on endothelial cells, promoting neutrophil rolling in vivo.
