TY - JOUR
T1 - Leukocyte Tetraspanin CD53 Restrains α3 Integrin Mobilization and Facilitates Cytoskeletal Remodeling and Transmigration in Mice
AU - Yeung, Louisa
AU - Anderson, Jeremy M L
AU - Wee, Janet L
AU - Demaria, Maria C
AU - Finsterbusch, Michaela
AU - Liu, Yuxin S
AU - Hall, Pam
AU - Smith, Brodie C
AU - Dankers, Wendy
AU - Elgass, Kirstin D
AU - Wicks, Ian P
AU - Kwok, Hang Fai
AU - Wright, Mark D
AU - Hickey, Michael J
N1 - Copyright © 2020 by The American Association of Immunologists, Inc.
PY - 2020/7/15
Y1 - 2020/7/15
N2 - The importance of tetraspanin proteins in regulating migration has been demonstrated in many diverse cellular systems. However, the function of the leukocyte-restricted tetraspanin CD53 remains obscure. We therefore hypothesized that CD53 plays a role in regulating leukocyte recruitment and tested this hypothesis by examining responses of CD53-deficient mice to a range of inflammatory stimuli. Deletion of CD53 significantly reduced neutrophil recruitment to the acutely inflamed peritoneal cavity. Intravital microscopy revealed that in response to several inflammatory and chemotactic stimuli, absence of CD53 had only minor effects on leukocyte rolling and adhesion in postcapillary venules. In contrast, Cd53-/- mice showed a defect in leukocyte transmigration induced by TNF, CXCL1 and CCL2, and a reduced capacity for leukocyte retention on the endothelial surface under shear flow. Comparison of adhesion molecule expression in wild-type and Cd53-/- neutrophils revealed no alteration in expression of β2 integrins, whereas L-selectin was almost completely absent from Cd53-/- neutrophils. In addition, Cd53-/- neutrophils showed defects in activation-induced cytoskeletal remodeling and translocation to the cell periphery, responses necessary for efficient transendothelial migration, as well as increased α3 integrin expression. These alterations were associated with effects on inflammation, so that in Cd53-/- mice, the onset of neutrophil-dependent serum-induced arthritis was delayed. Together, these findings demonstrate a role for tetraspanin CD53 in promotion of neutrophil transendothelial migration and inflammation, associated with CD53-mediated regulation of L-selectin expression, attachment to the endothelial surface, integrin expression and trafficking, and cytoskeletal function.
AB - The importance of tetraspanin proteins in regulating migration has been demonstrated in many diverse cellular systems. However, the function of the leukocyte-restricted tetraspanin CD53 remains obscure. We therefore hypothesized that CD53 plays a role in regulating leukocyte recruitment and tested this hypothesis by examining responses of CD53-deficient mice to a range of inflammatory stimuli. Deletion of CD53 significantly reduced neutrophil recruitment to the acutely inflamed peritoneal cavity. Intravital microscopy revealed that in response to several inflammatory and chemotactic stimuli, absence of CD53 had only minor effects on leukocyte rolling and adhesion in postcapillary venules. In contrast, Cd53-/- mice showed a defect in leukocyte transmigration induced by TNF, CXCL1 and CCL2, and a reduced capacity for leukocyte retention on the endothelial surface under shear flow. Comparison of adhesion molecule expression in wild-type and Cd53-/- neutrophils revealed no alteration in expression of β2 integrins, whereas L-selectin was almost completely absent from Cd53-/- neutrophils. In addition, Cd53-/- neutrophils showed defects in activation-induced cytoskeletal remodeling and translocation to the cell periphery, responses necessary for efficient transendothelial migration, as well as increased α3 integrin expression. These alterations were associated with effects on inflammation, so that in Cd53-/- mice, the onset of neutrophil-dependent serum-induced arthritis was delayed. Together, these findings demonstrate a role for tetraspanin CD53 in promotion of neutrophil transendothelial migration and inflammation, associated with CD53-mediated regulation of L-selectin expression, attachment to the endothelial surface, integrin expression and trafficking, and cytoskeletal function.
KW - Animals
KW - Arthritis, Experimental/immunology
KW - Arthritis, Rheumatoid/immunology
KW - Chemokine CCL2/metabolism
KW - Chemokine CXCL1/metabolism
KW - Cytoskeleton/metabolism
KW - Humans
KW - Integrin alpha3/metabolism
KW - L-Selectin/metabolism
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Neutrophils/physiology
KW - Tetraspanin 25/metabolism
KW - Transendothelial and Transepithelial Migration
U2 - https://doi.org/10.4049/jimmunol.1901054
DO - https://doi.org/10.4049/jimmunol.1901054
M3 - Article
C2 - 32532837
SN - 0022-1767
VL - 205
SP - 521
EP - 532
JO - Journal of immunology (Baltimore, Md.
JF - Journal of immunology (Baltimore, Md.
IS - 2
ER -