Although adhesion in itself may be independent of signaling, it was demonstrated that PECAM-1–PECAM-1 interactions increase expression of the integrin α6β1, which is involved in the migration process, on transmigrated neutrophils 25, and that PECAM-1 is essential for neutrophil chemotaxis 26. While the suppressive effect on migration exerted by PIR-B is in accordance with the anticipated function of an inhibitory receptor, the enhanced migration induced by
Ly49Q and PECAM-1 activation is perhaps unexpected. This raises Apoptosis inhibitor the question whether these inhibitory receptors specifically enhance migration and suppress other effector functions. Indeed, PECAM-1 has opposing effects on inflammatory cytokine production and cell migration, illustrating that not all cellular functions are suppressed. Individuals carrying genetic mutations that lead to a disturbed inhibitory receptor function may be prone to develop excess leukocyte activation. Since some inhibitory receptors may be positively involved in cell migration, one could speculate that in individuals carrying mutations affecting such receptors, a reduced migratory capacity for cells with deficient
inhibitory find more receptor signaling prevents tissue damage by infiltrated leukocytes. This perspective shows some similarity with the licensing theory in NK cells (which states that NK cells are “licensed” for functional competence by prior signaling through an inhibitory receptor 27) in which immune cells that have proper inhibitory
receptor function are licensed to migrate to the tissues. An ongoing immune response must be appropriately terminated to restore immune homeostasis. This process includes clearing of excess immune cells by apoptosis. Several inhibitory receptors may be involved in this process. CD33-related Siglec-8 and Siglec-9 are inhibitory receptors that have frequently Protein kinase N1 been associated with increased apoptosis in myeloid cells 28. In vitro, antibody-mediated cross-linking of Siglec-9 results in increased apoptosis in resting neutrophils 29 (Fig. 1). Moreover, inflammatory neutrophils obtained from patients with acute septic shock or rheumatoid arthritis demonstrated enhanced Siglec-9-mediated neutrophil death compared with healthy controls 29. The increased Siglec-9-mediated cell death could be reproduced by priming of neutrophils with pro-inflammatory cytokines, such as GM-CSF, IFN-α, or IFN-γ in vitro 29. This indicates that Siglec-9 may indeed have a role in regulating apoptosis of activated neutrophils to balance the immune response.