title: Cleavage of the CD11b extracellular domain by the leukocyte serprocidins is critical for neutrophil detachment during chemotaxis.
abstract: The β(2)-integrin CD11b/CD18 mediates the firm adhesion of neutrophils (PMNs) to epithelial monolayers, a key step in PMN transepithelial migration. To complete the transmigration process, adherent PMNs must detach from epithelial monolayer surfaces to move forward. The mechanism that governs the detachment of adherent PMNs, however, is not clear. Here, we present evidence that cleavage of the CD11b extracellular domain containing the ligand-binding I-domain by 3 structural and functional related serine proteases (elastase, proteinase-3 and cathepsin G) serves as a novel mechanism for PMN detachment after the initial cell adhesion. Kinetic studies showed that the cleavage of CD11b is positively correlated with PMN detachment and subsequent transmigration. Moreover, the results demonstrated that elastase, proteinase-3 and cathepsin G all cleaved the purified, functionally active form of CD11b in a pattern similar to the CD11b shedding that occurs during PMN transmigration. Their cleavage sites on purified CD11b were located at (761)Thr-Ala(762) (elastase/proteinase-3) and (760)Phe-Thr(761) (cathepsin G), respectively. CD11b cleavage and PMN detachment and chemotaxis, were impaired in elastase/cathepsin G-deficient Beige mice; this defect could be restored by the addition of extracellular elastase. By illustrating CD11b shedding by elastase, proteinase-3 and cathepsin G as a novel mechanism for PMN detachment, our study provides novel therapeutic targets for controlling inflammation.
authors.affiliation: Nanjing University, Jiangsu, China. kzen@nju.edu.cn
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
authors.forename: Ya-Lan
authors.initials: YL
authors.lastname: Guo
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Li
authors.forename: Zhen
authors.initials: Z
authors.lastname: Bian
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D001665:Binding Sites; D039481:CD11b Antigen / Q000737:chemistry / Q000378:metabolism*; D018821:CD18 Antigens / Q000378:metabolism; D056649:Cathepsin G / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D019272:Leukocyte Elastase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D053146:Myeloblastin / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D017434:Protein Structure, Tertiary; D057057:Serine Proteases / Q000378:metabolism*
chemical_list: D039481:CD11b Antigen; D018821:CD18 Antigens; C509295:ITGAM protein, human; D057057:Serine Proteases; C534094:CTSG protein, human; D056649:Cathepsin G; C534096:Ctsg protein, mouse; D019272:Leukocyte Elastase; D053146:Myeloblastin