The Ly49Q Receptor Plays a Crucial Role in Neutrophil Polarization and Migration by Regulating Raft Trafficking

Abstract

Neutrophils rapidly undergo polarization and directional movement to infiltrate the sites of infection and inflammation. Here, we show that an inhibitory MHC I receptor, Ly49Q, was crucial for the swift polarization of and tissue infiltration by neutrophils. During the steady state, Ly49Q inhibited neutrophil adhesion by preventing focal-complex formation, likely by inhibiting Src and PI3 kinases. However, in the presence of inflammatory stimuli, Ly49Q mediated rapid neutrophil polarization and tissue infiltration in an ITIM-domain-dependent manner. These opposite functions appeared to be mediated by distinct use of effector phosphatase SHP-1 and SHP-2. Ly49Q-dependent polarization and migration were affected by Ly49Q regulation of membrane raft functions. We propose that Ly49Q is pivotal in switching neutrophils to their polarized morphology and rapid migration upon inflammation, through its spatiotemporal regulation of membrane rafts and raft-associated signaling molecules.

Siglec-E is a negative regulator of acute pulmonary neutrophil inflammation and suppresses CD11b β2-integrin–dependent signaling

“…Ly49Q has been shown to inhibit neutrophil adhesion by preventing focal-complex formation, whereas following exposure to inflammatory stimuli, Ly49Q can switch functions and promote neutrophil polarization and tissue infiltration. 9 In comparison, CEACAM1 plays a key role in SHP-1-dependent expansion of bone marrow neutrophils via blocking granulocyte macrophage-CSF-signal transducer and activator of transcription 3 signaling. 42 A recent study has shown that CEACAM1 can also regulate TLR-4-triggered inflammasome activation via SHP-1-dependent negative regulation of Syk activation.…”

“…7,8 Moreover, via association with SHP-1, Ly49Q has been reported to regulate inappropriate activation and adhesion of neutrophils by preventing focal complex formation. 9 Other recent reports describe GDF-15 as a novel inhibitor of neutrophil recruitment by preventing chemokine triggered b2-integrin activation and clustering 10 and Btk as a "gatekeeper," important for preventing the priming of neutrophils and modulation of their production of reactive oxygen species to prevent death by apoptosis.…”

Reactive Oxygen Species in Inflammation and Tissue Injury

“…After b 2 -integrin-mediated neutrophil arrest, there is a polarization of neutrophils at the leading edge referred to as lamellipodium that orchestrates receptors for chemokines and phagocytosis. Polarization of neutrophils, which is important for efficient transendothelial migration, is mediated by the organization of filamentous actin (F-actin) cytoskeleton at the leading edge (375,461).…”

The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation

“…Thus, impaired SHP-1 activity in Rap1b / neutrophils may maximize Akt signaling. SHP-1 is classically recruited to the plasma membrane by immunoreceptor tyrosine-based inhibition motifs (ITIMs) bearing receptors, including Siglec-E, PIR-B, or Ly49d (Zhang et al, 2005;Sasawatari et al, 2010;McMillan et al, 2013). Loss of functions of such receptors causes increased neutrophil migration and inflammation (Zhang et al, 2005;Sasawatari et al, 2010;McMillan et al, 2013).…”