For example, Sialic-acid-binding Ig-like lectin (Siglec)-10 is expressed by monocytes 19. This inhibitory receptor can inhibit inflammatory cytokine production induced by danger-associated molecular pattern (DAMP) signaling, such as HMGB1, through binding of CD24, whereas signaling via PAMPs, Autophagy Compound Library such as LPS or poly I:C, is unaffected in vitro 20. While WT mice were unaffected, CD24-deficient mice rapidly succumbed to a sublethal dose of acetaminophen in a liver necrosis model 20. This specific regulation protects the host against a lethal response to cell death, whereas it allows a potent immune response upon infection. Besides regulating pro-inflammatory cytokine

production, inhibitory receptors may also regulate the production of anti-inflammatory cytokines. For example, Alectinib mouse upon TLR activation, Siglec-9 not only reduces the production of pro-inflammatory cytokines, but also enhances IL-10 production through ITIM signaling in the mouse macrophage cell line RAW264 21. Together, these studies demonstrate that inhibitory receptors can potently suppress

TLR-induced inflammatory cytokine production, either directly by inhibition of the TLR signaling or indirectly by increased production of anti-inflammatory cytokines. On the contrary, some inhibitory receptors may enhance inflammatory cytokine production. Finally, some inhibitory receptors Edoxaban do not seem involved in regulating pathogen-associated cell activation, but specifically modulate danger-associated molecular pattern signaling. The distinct capacities of various inhibitory receptors will therefore contribute to an orchestrated immune response during successive stages

of infection. Tissue infiltration by phagocytes requires tight regulation to limit the tissue damage by the release of inflammatory mediators. Infiltration may be reduced directly through modulation of G protein-coupled receptor (GPCR)-mediated chemotaxis, adherence, or transmigration, or indirectly by desensitization of phagocytes to these processes. Intriguingly, specific inhibitory receptors seem to have opposite effects on granulocyte migration. Mouse neutrophils deficient in paired Ig-like receptor-B (PIR-B) (the mouse ortholog of Ig-like transcript [ILT]2–5) have enhanced chemotactic responses in vitro after stimulation with macrophage inflammatory protein (MIP)-1α, MIP-2, CCL19, and CCL21 22, indicative of a suppressive function for this receptor (Fig. 1). On the contrary, Ly49Q is indispensable for neutrophil polarization and migration after N-formylated methionyl-leucyl-phenylalanine (fMLP) or cytokine-induced neutrophil chemoattractant (KC) stimulation in vitro although Ly49Q inhibits neutrophil adhesion in steady-state conditions 23. Neutrophil polarization and infiltration into inflamed air-pouches is also impaired in vivo in Ly49Q knockout mice 23.