IntroductionNatural killer (NK) cells represent a minor population (5%-20%) of peripheral blood lymphocytes that is also present in secondary lymphoid organs, such as spleen, and lymph nodes, as well as in liver, bone marrow, and maternal uterus. [1][2][3] The function of NK cells in humans is regulated by a balance between opposite signals delivered by a set of HLA class I-specific inhibitory receptors and by a number of activating receptors and coreceptors responsible for NK cell triggering. By the combined use of these receptors, NK cells can discriminate between normal HLA class I ϩ cells and cells that have lost the expression of HLA class I molecules as a consequence of tumor transformation or viral infection. [4][5][6][7] Most NK cells in peripheral blood express the CD56 low CD16 ϩ phenotype, whereas the remainders are CD56 high CD16 Ϫ cells. It was proposed that CD56 high NK cells represent a primary source of immunoregulatory cytokines, whereas the CD56 low C16 ϩ subset represents the principal cytotoxic population. 8 During inflammation, viral infection and tumor growth, NK cells are rapidly recruited from the blood into injured tissues. 9-11 NK cell recruitment is governed by integrated signals, which include adhesion molecules and chemotactic factors. CD56 low CD16 ϩ NK cells express both 1 and 2 integrins, as well as the ligands for E-and P-selectins. In addition to these molecules, CD56 high NK cells also express high levels of L-selectin, a pivotal molecule for the interaction with lymph node high endothelial venules. 12-14 With respect to chemokine receptors, CD56 low CD16 ϩ NK cells express high levels of CXCR1 and CX3CR1. 9,15 By contrast, CD56 high NK cells express CCR7 as well as CCR5 and CXCR3. 8,9,15 It is likely that the different expression profile of adhesion molecules and chemokine receptors between the 2 major blood NK cell subsets is responsible for the preferential migration of CD56 low CD16 ϩ and CD56 high CD16 Ϫ NK cells into inflamed tissues and secondary lymphoid organs, respectively. 16 In fact, the CD56 high CD16 Ϫ NK cell subset although poorly represented in peripheral blood constitutes the only type of NK cells present in secondary lymphoid tissues. 2,3 We have recently identified a novel protein, chemerin, as the natural ligand of the previously orphan receptor ChemR23. 17 ChemR23 exhibits a unique expression profile among leukocyte populations being expressed preferentially by monocyte/macrophages and by immature myeloid and plasmacytoid dendritic cells (DCs). 18 Chemerin, originally isolated from inflamed biologic fluids, such as ovarian cancer ascites and rheumatoid arthritis synovial fluids, is synthesized as a secreted precursor protein.Prochemerin is poorly active but can be rapidly converted into a full ChemR23 agonist by the proteolytic removal of the last 6 amino acids by neutrophil-derived proteases (elastase and cathepsin G), mast cell products (triptase), and proteases of the coagulation cascade. 19,20 Therefore, prochemerin represents a "ready to The online ...