Biomedical Engineering Reference
In-Depth Information
a group of heterodimeric transmembrane glycoproteins that are expressed on
neutrophils and other hematopoietic cells, and function to coordinate cell-to-cell
and cell-to-extracellular matrix adhesions. h ere are 16 α subunits and 8 β subunits
that give rise to a variety of integrins. In the case of β
2
integrins, there is only a
common β chain (CD18) and a single, but variable, α chain (CD11a, b, c, or d).
Only macrophage antigen (Mac)-1 (i.e., αMβ2 and CD11b/CD18) and lymphocyte-
associated function antigen (LFA)-1 (αLβ2 and CD11a/CD18) mediate neutrophil
binding to the endothelium. Neutrophils store Mac-1 in specii c gelatin granules
and in secretory vesicles, but Mac-1 can be rapidly mobilized to the cell surface
in response to various inl ammatory mediators, such as the bacterial peptide
formyl-methionyl-leucyl-phenylalanine (fMLP). An important endothelial ligand
for Mac-1 is intracellular adhesion molecule 1 (ICAM-1), which belongs to the
Ig superfamily. ICAM-1 exhibits low constitutive expression on endothelial cell
membranes but it is markedly induced by exposure to cytokines. LFA-1 can also
bind to ICAM-1 but it has a higher ai nity to the related protein ICAM-2. In
addition, other members of the Ig superfamily are involved in leukocyte adhesion.
For example, vascular cell adhesion molecule (VCAM)-1 binds to very late antigen
(VLA)-4 on activated human and rat neutrophils.
h e next stage in neutrophil emigration from the endothelium involves
adhesion strengthening, which is mediated by integrins through 'outside-in'
signaling pathways (Ley
et al.
2007). It is well recognized that integrins generate
intracellular signals that regulate various cellular functions, including cell motility,
proliferation, and apoptosis (Shattil 2005). Ligand-induced integrin clustering and
allosteric conformational changes likely contribute to the initiation of outside-in
signaling and the formation of signalosomes, which are required for the ei cient
recruitment of protein tyrosine kinases and the initiation of the full repertoire of
signaling pathways (Liu
et al.
2002a). For instance, recent studies suggest that the
induction of conformational changes to the cytosolic tail of LFA-1 heterodimer
upon ICAM-1 binding may play a role in the rapid arrest of leukocytes under l ow
(Shamri
et al.
2005). Two SRC-like protein tyrosine kinases (FGR and hemopoietic
cell kinase) are important inducers of outside-in signaling by LFA-1 and Mac-1
(Giagulli
et al.
2006). It is also inferred that the lack of outside-in signaling
mediated by the β
2
integrin chain greatly accelerates the detachment of adherent
neutrophil under l ow (Giagulli
et al.
2006). For further details regarding outside-
in signaling in the adhesion-strengthening step involved in neutrophil emigration,
see Ley
et al.
(2007) for review.
Intravascular crawling follows the adhesion-strengthening step, and this step
results in the migration of neutrophils across the endothelium (Ley
et al.
2007).
h is stage of neutrophil migration is known as transendothelial migration and
involves several adhesion molecules that regulate paracellular trai cking, such as
CD99, platelet adhesion molecule 1 (PECAM-1), as well as junctional adhesion
molecules (JAM-A, JAM-B, JAM-C), and endothelial cell-selective adhesion
