The chemoattractant chemerin suppresses melanoma by recruiting natural killer cell antitumor defenses

Pachynski, Russell K.; Zabel, Brian A.; Kohrt, Holbrook E.; Tejeda, Nicole; Monnier, Justin; Swanson, Christina; Holzer, Alison K.; Gentles, Andrew J.; Sperinde, Gizette; Edalati, Abdolhossein; Hadeiba, Husein; Alizadeh, Ash A.; Butcher, Eugene C.

doi:10.1084/jem.20112124

Cited by 137 publications

(196 citation statements)

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“…NK cell recruitment and tumor infiltration have been associated with a less severe disease in human tumors of different histotypes and in a number of mouse tumor models (11)(12)(13)(14)(15)(16)(17). A number of G protein-coupled receptors belonging to the chemokine receptor family on NK cell surface and their corresponding tissue counter ligands regulate NK cell mobilization into blood from storage tissues including bone marrow and spleen, and their extravasation and infiltration of tumor-bearing tissues to initiate an antitumor response (1,18).…”

Section: /Cd3mentioning

confidence: 99%

Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment

et al. 2015

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Section: /Cd3mentioning

confidence: 99%

Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment

et al. 2015

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“…Chemokine receptors such as CCR7, CCR5, and CXCR3 are involved in the preferential migrations and localization of NK cells into the LNs [8,[16][17][18][19], whereas NK cells reside in blood, liver, and spleen exhibit higher CXCR1 and CX 3 CR1 expression [8,9,[20][21][22][23][24][25]. Nonchemokine family proteins such as chemerin and SIP 5 are also involved in the regulation of NK-cell trafficking [26,27]. Collectively, they highlight the complexity of the environmental regulation of NK-cell migrations in physiological and pathological conditions.…”

mentioning

confidence: 99%

Microfluidic‐based, live‐cell analysis allows assessment of NK‐cell migration in response to crosstalk with dendritic cells

et al. 2014

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Migration and localization of NK cells into peripheral tissues are tightly regulated under normal and pathological conditions. The physiological importance of NK cell-DC crosstalk has been well documented. However, the ways in which DCs regulate the migratory properties of NK cells (such as chemotaxis, chemokinesis, chemo-repulsion) are not fully defined in vitro. Here, we employed a microfluidic platform to examine, at the single-cell level, C57BL/6 NK-cell migrations in a stable chemical gradient. We observed that soluble factors released by the immature and LPS-activated mature DCs induced a high level of chemotactic movement of IL-2-activated NK cells in vitro. We confirmed these findings in a standard trans-well migration assay, and identified CXCR3 as a key receptor on the NK cells that mediated the migration. More interestingly, we revealed a novel function of granulocyte macrophage colony-stimulating factor in repulsing NK-cell migrations. The future uses of such microfluidic device in the systematic evaluations of NK-cell migratory responses in NK cell-DC crosstalk will provide new insights into the development of DC-based NK-cell therapies against tumor and infections.Keywords: Bone marrow-derived dendritic cells r Chemo-repulsion r Chemotaxis r Microfluidic device r Natural killer cell r NK-DC crosstalk Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction NK cells are motile bone marrow (BM)-derived lymphocytes that play a key role in innate immunity against viral, microbial infections, and transformed cells [1][2][3]. They are capable of killing transformed or infected cells [1,2,4,5], and/or producing cytokines/chemokines that can profoundly influence the quality and magnitude of the adaptive immune responses [6][7][8][9]. They Correspondence: Dr. Sam K. P. Kung e-mail: Sam.Kung2@med.umanitoba.ca acquire specific chemokine surface receptors during development and maturation [2,[10][11][12][13][14][15]. Chemokine receptors such as CCR7, CCR5, and CXCR3 are involved in the preferential migrations and localization of NK cells into the LNs [8,[16][17][18][19], whereas NK cells reside in blood, liver, and spleen exhibit higher CXCR1 and CX 3 CR1 expression [8,9,[20][21][22][23][24][25]. Nonchemokine family proteins such as chemerin and SIP 5 are also involved in the regulation of NK-cell trafficking [26,27]. Collectively, they highlight the complexity of the environmental regulation of NK-cell migrations in physiological and pathological conditions. NK-cell activation and functions are regulated by cytokine/ chemokine and/or DC in the microenvironments [18,[28][29][30] [36,37]. In this report, we demonstrated an application of such microfluidic device in examining how soluble factors produced by DC regulated NK-cell migrations in vitro. Results A microfluidic platform to perform live-cell imaging of NK-cell migrationsWe used the established Y-shaped microfluidic device to examine chemotactic or chemo-repulsive movements of NK cells ...

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“…Thus, wild-type mice were subjected to the protocol for the induction of exacerbated experimental asthma and were additionally treated with an anti-Asialo GM1 polyclonal antiserum, which is a standard method to deplete NK cells (16). This NK cell depletion led to a reduced overall response compared with untreated mice undergoing the induction of experimental asthma (Fig.…”

Section: Il-17a Producing Nk Cells Play a Critical Role In Pic-triggementioning

confidence: 99%

Poly(inosinic-cytidylic) Acid–Triggered Exacerbation of Experimental Asthma Depends on IL-17A Produced by NK Cells

Lunding

Webering

Vock

et al. 2015

The Journal of Immunology

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Viral infection of the respiratory tract represents the major cause of acute asthma exacerbations. dsRNA is produced as an intermediate during replication of respiratory viruses and triggers immune responses via TLR3. This study aimed at clarifying the mechanisms underlying TLR3 triggered exacerbation of experimental allergic asthma. The TLR3 ligand poly(inosinic-cytidylic) acid was applied intranasally to mice with already established experimental allergic asthma. Airway inflammation, cytokine expression, mucus production, and airway reactivity was assessed in wild-type, IL-17A, or IL-23p19–deficient, and in NK cell–depleted mice. Local application of poly(inosinic-cytidylic) acid exacerbated experimental allergic asthma in mice as characterized by enhanced release of proinflammatory cytokines, aggravated airway inflammation, and increased mucus production together with pronounced airway hyperresponsiveness. This was further associated with augmented production of IL-17 by Th17 cells and NK cells. Whereas experimental exacerbation could be induced in IL-23p19–deficient mice lacking mature, proinflammatory Th17 cells, this was not possible in mice lacking IL-17A or in NK cell–depleted animals. These experiments indicate a central role for IL-17 derived from NK cells but not from Th17 cells in the pathogenesis of virus-triggered exacerbation of experimental asthma.

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The chemoattractant chemerin suppresses melanoma by recruiting natural killer cell antitumor defenses

Abstract: Chemerin recruits NK cells to suppress melanoma growth.

Cited by 137 publications

References 32 publications

Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment

Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment

Microfluidic‐based, live‐cell analysis allows assessment of NK‐cell migration in response to crosstalk with dendritic cells

Poly(inosinic-cytidylic) Acid–Triggered Exacerbation of Experimental Asthma Depends on IL-17A Produced by NK Cells

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