The role of selectins in inflammation and disease

https://doi.org/10.1016/S1471-4914(03)00071-6Get rights and content

Abstract

Selectins are carbohydrate-binding molecules that bind to fucosylated and sialylated glycoprotein ligands, and are found on endothelial cells, leukocytes and platelets. They are involved in trafficking of cells of the innate immune system, T lymphocytes and platelets. An absence of selectins or selectin ligands has serious consequences in mice or humans, leading to recurrent bacterial infections and persistent disease. Selectins are involved in constitutive lymphocyte homing, and in chronic and acute inflammation processes, including post-ischemic inflammation in muscle, kidney and heart, skin inflammation, atherosclerosis, glomerulonephritis and lupus erythematosus. Selectin-neutralizing monoclonal antibodies, recombinant soluble P-selectin glycoprotein ligand 1 and small-molecule inhibitors of selectins have been tested in clinical trials on patients with multiple trauma, cardiac indications and pediatric asthma, respectively. Anti-selectin antibodies have also been successfully used in preclinical models to deliver imaging contrast agents and therapeutics to sites of inflammation. Further improvements in the efficiency, availability, specificity and pharmacokinetics of selectin inhibitors, and specialized application routes and schedules, hold promise for therapeutic indications.

Section snippets

Selectin ligands

There are many candidate ligands for selectins, but only P-selectin glycoprotein ligand 1 (PSGL-1) has been extensively characterized at the molecular, cellular and functional level (Fig. 2). Knockout mice lacking the gene encoding PSGL-1 3, 4 show delayed neutrophil recruitment and moderate neutrophilia (threefold elevation), similar to that of P-selectin knockout mice 5, 6. In addition to being responsible for ∼90% of P-selectin binding, PSGL-1 is also the most important L-selectin ligand in

Inflammation

In most organs, leukocyte recruitment proceeds in a cascade-like fashion from capture to rolling to a systematic decrease of rolling velocity to firm adhesion and transmigration [10]. The selectins participate in the capture, rolling and slow-rolling steps [11]. In addition, there is evidence that selectin engagement can trigger signaling events in the leukocyte through L-selectin [12] and PSGL-1 [13], and in endothelial cells through E-selectin [14].

Effective neutrophil recruitment requires

Selectin-dependent monocyte functions

Monocytes express functional PSGL-1 and use selectins to leave the vascular system. In models of atherosclerosis, blocking of P-selectin reduces monocyte rolling and adhesion to the arterial endothelium [37]; P-selectin-deficient mice show a reduction in the size of atherosclerotic lesions [38] and decreased neointima formation after arterial injury [39]. The role of E-selectin is less significant, and mice lacking this molecule show only a modest reduction in atherosclerotic lesion size.

Selectin-dependent platelet functions

Activated platelets express P-selectin, which binds PSGL-1 on leukocytes and monocytes (Fig. 3). This interaction is responsible for the recruitment of inflammatory leukocytes to thrombi [40], where they are thought to help organize and resolve the thrombus, although the role of selectins has not been formally tested in models of this process. An additional function of platelet P-selectin is in the recruitment of monocyte-derived microparticles, which are a rich source of the blood-clotting

Selectin functions in the adaptive immune system

Mice lacking L-selectin show a severe defect in the homing of naive T lymphocytes to peripheral lymph nodes, a moderate defect in homing to mesenteric lymph nodes, and a subtle defect in homing to Peyer's patches; cells expressing L-selectin cannot roll on high endothelial venules in lymph nodes, which express L-selectin ligands that are different from PSGL-1 8, 43. Central memory T cells also express L-selectin, and their homing to peripheral lymph nodes might also be impaired in

Organ specificity

Intravital microscopic, cell homing and disease studies all suggest that selectin recruitment differs among organs. For example, neutrophil recruitment to the liver and lung is largely selectin-independent 51, 52, although exceptions exist in some lung models. In general terms, based on the pathologies seen in mice and humans, P- and E-selectin are important in neutrophil recruitment to skin and mucosal membranes, and to kidney, skeletal muscle and heart, but not to liver or to lung after

Use of selectins for targeted delivery and diagnostics

P- and E-selectins are expressed at reasonably high density on the luminal plasma membrane of vascular endothelial cells at sites of inflammation, and are therefore, in principle, suitable targets for the delivery of drugs, plasmids for gene therapy, and imaging contrast agents. Indeed, P-selectin has successfully been targeted by ultrasound contrast agents [57], enabling the selective and specific imaging of inflamed kidney and heart muscle. Antibody conjugates have also been used to deliver

Therapeutic use of selectin inhibitors

Four classes of selectin inhibitors have been developed and tested in preclinical models and some clinical trials. The first developed were carbohydrate-based selectin inhibitors of the sialyl Lewisx type, which inhibit all three selectins at high concentrations. However, their unfavorable pharmacokinetics, low affinity and relatively high production costs made them unsuitable for further development.

Second, antibodies to selectins have been developed and humanized, including antibodies that

Conclusions

Selectins are crucial for the innate immune response, as demonstrated in selectin-deficient and selectin-ligand-deficient patients and in mouse models. Disease treatment using selectin inhibition shows most promise in ischemia–reperfusion-type situations and in skin diseases. However, chronic selectin inhibition will probably produce unfavorable consequences by suppressing the innate immune system. The effects of transient selectin inhibition in well-controlled clinical settings, such as organ

References (61)

  • M. Rauchhaus

    The E-selectin Ser128Arg gene polymorphism and restenosis after successful coronary angioplasty

    Int. J. Cardiol.

    (2002)
  • E. Larsen

    PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes

    Cell

    (1989)
  • S.B. Forlow

    Increased granulopoiesis through interleukin-17 and granulocyte colony stimulating factor in adhesion molecule-deficient mice

    Blood

    (2001)
  • M.L. Arbones

    Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice

    Immunity

    (1994)
  • K.E. Norman

    Sialyl Lewisx (sLex) and an sLex mimetic, CGP69669A, disrupt E-selectin-dependent leukocyte rolling in vivo

    Blood

    (1998)
  • E.T. Keelan

    Characterization of E-selectin expression in vivo with use of a radiolabeled monoclonal antibody

    Am. J. Physiol.

    (1994)
  • L. Xia

    P-selectin glycoprotein ligand-1 deficient mice have impaired leukocyte tethering to E-selectin under flow

    J. Clin. Invest.

    (2002)
  • J. Yang

    Targeted gene disruption demonstrates that P-selectin glycoprotein ligand 1 (PSGL-1) is required for P-selectin- mediated but not E-selectin-mediated neutrophil rolling and migration

    J. Exp. Med.

    (1999)
  • D.C. Bullard

    P-selectin/ICAM-1 double mutant mice: acute emigration of neutrophils into the peritoneum is completely absent but is normal in pulmonary alveoli

    J. Clin. Invest.

    (1995)
  • Sperandio, M. et al. P-selectin glycoprotein ligand-1 mediates L-selectin-dependent leukocyte rolling in venules. J....
  • C. Sassetti

    Identification of podocalyxin-like protein as a high endothelial venule ligand for L-selectin – parallels to CD34

    J. Exp. Med.

    (1998)
  • K. Ley

    Integration of inflammatory signals by rolling neutrophils

    Immunol. Rev.

    (2002)
  • S.I. Simon

    Signaling functions of L-selectin in neutrophils: alterations in the cytoskeleton and colocalization with CD18

    J. Immunol.

    (1999)
  • K.L. Moore

    Structure and function of P-selectin glycoprotein ligand-1

    Leuk. Lymphoma

    (1998)
  • M. Yoshida

    Phosphorylation of the cytoplasmic domain of E-selectin is regulated during leukocyte–endothelial adhesion

    J. Immunol.

    (1998)
  • U. Jung et al.

    Mice lacking two or all three selectins demonstrate overlapping and distinct functions of each selectin

    J. Immunol.

    (1999)
  • S.D. Robinson

    Multiple, targeted deficiencies in selectins reveal a predominant role for P-selectin in leukocyte recruitment

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • J.B. Lowe

    Glycosylation in the control of selectin counter-receptor structure and function

    Immunol. Rev.

    (2002)
  • K. Luhn

    The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter

    Nat. Genet.

    (2001)
  • M.K. Wild

    Leukocyte adhesion deficiency II: therapy and genetic defect

    Cells Tissues Organs

    (2002)
  • Cited by (581)

    View all citing articles on Scopus
    View full text