LSP1 is an endothelial gatekeeper of leukocyte transendothelial migration.
Leukocyte-specific protein 1 (LSP1), an F-actin binding protein and a major downstream substrate of p38 mitogen-activated protein kinase as well as protein kinase C, has been reported to be important in leukocyte chemotaxis. Although its distribution has been thought to be restricted to leukocytes, herein we report that LSP1 is expressed in endothelium and is essential to permit neutrophil emigration. Using intravital microscopy to directly visualize leukocyte rolling, adhesion, and emigration in postcapillary venules in LSP1-deficient (Lsp1-/-) mice, we found that LSP1 deficiency inhibits neutrophil extravasation in response to various cytokines (tumor necrosis factor-alpha and interleukin-1beta) and to neutrophil chemokine keratinocyte-derived chemokine in vivo. LSP1 deficiency did not affect leukocyte rolling or adhesion. Generation of Lsp1-/- chimeric mice using bone marrow transplantation revealed that in mice with Lsp1-/- endothelial cells and wild-type leukocytes, neutrophil transendothelial migration out of postcapillary venules is markedly restricted. In contrast, Lsp1-/- neutrophils in wild-type mice were able to extravasate normally. Consistent with altered endothelial function was a reduction in vascular permeability to histamine in Lsp1-/- animals. Western blot analysis and immunofluorescence microscopy examination confirmed the presence of LSP1 in wild-type but not in Lsp1-/- mouse microvascular endothelial cells. Cultured human endothelial cells also stained positive for LSP1. Our results suggest that LSP1 expressed in endothelium regulates neutrophil transendothelial migration.
Liu
Lixin
L
Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Cara
Denise C
DC
Kaur
Jaswinder
J
Raharjo
Eko
E
Mullaly
Sarah C
SC
Jongstra-Bilen
Jenny
J
Jongstra
Jan
J
Kubes
Paul
P
D000818:Animals; D016026:Bone Marrow Transplantation; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002199:Capillary Permeability; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004727:Endothelium / Q000166:cytology / Q000378:metabolism*; D006439:Hemodynamics; D006632:Histamine / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D018375:Neutrophil Activation; D020556:Neutrophil Infiltration; D018183:Transplantation Chimera; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014699:Venules / Q000378:metabolism
D002135:Calcium-Binding Proteins; D018925:Chemokines; D007375:Interleukin-1; C057701:Lsp1 protein, mouse; D008840:Microfilament Proteins; D014409:Tumor Necrosis Factor-alpha; D006632:Histamine