Laquinimod, a prototypic quinoline-3-carboxamide and aryl hydrocarbon receptor agonist, utilizes a CD155-mediated natural killer/dendritic cell interaction to suppress CNS autoimmunity.

Abstract

BACKGROUND:

Quinoline-3-carboxamides, such as laquinimod, ameliorate CNS autoimmunity in patients and reduce tumor cell metastasis experimentally. Previous studies have focused on the immunomodulatory effect of laquinimod on myeloid cells. The data contained herein suggest that quinoline-3-carboxamides improve the immunomodulatory and anti-tumor effects of NK cells by upregulating the adhesion molecule DNAX accessory molecule-1 (DNAM-1).

METHODS:

We explored how NK cell activation by laquinimod inhibits CNS autoimmunity in experimental autoimmune encephalomyelitis (EAE), the most utilized model of MS, and improves immunosurveillance of experimental lung melanoma metastasis. Functional manipulations included in vivo NK and DC depletion experiments and in vitro assays of NK cell function. Clinical, histological, and flow cytometric read-outs were assessed.

RESULTS:

We demonstrate that laquinimod activates natural killer (NK) cells via the aryl hydrocarbon receptor and increases their DNAM-1 cell surface expression. This activation improves the cytotoxicity of NK cells against B16F10 melanoma cells and augments their immunoregulatory functions in EAE by interacting with CD155+ dendritic cells (DC). Noteworthy, the immunosuppressive effect of laquinimod-activated NK cells was due to decreasing MHC class II antigen presentation by DC and not by increasing DC killing.

CONCLUSIONS:

This study clarifies how DNAM-1 modifies the bidirectional crosstalk of NK cells with CD155+ DC, which can be exploited to suppress CNS autoimmunity and strengthen tumor surveillance.

• Authors: Martina Ott, Erika Avendaño-Guzmán, Evelyn Ullrich, Carolin Dreyer, Judith Strauss, Markus Harden, Margarete Schön, Michael P Schön, Günter Bernhardt, Christine Stadelmann, Christiane Wegner, Wolfgang Brück, Stefan Nessler
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 16 Issue 1 Pg. 49 (Feb 26 2019) ISSN: 1742-2094 [Electronic] England
• PMID: 30808363 (Publication Type: Journal Article)

Chemical References

• Antigens, Differentiation, T-Lymphocyte
• CD226 antigen
• Quinolines
• Quinolones
• Receptors, Aryl Hydrocarbon
• Receptors, Virus
• poliovirus receptor
• quinoline-3-carboxamide
• laquinimod

Topics

• Animals
• Antigens, Differentiation, T-Lymphocyte (immunology, metabolism)
• Autoimmunity (drug effects, immunology)
• Dendritic Cells (drug effects, immunology)
• Encephalomyelitis, Autoimmune, Experimental (immunology)
• Humans
• Immunologic Surveillance (immunology)
• Killer Cells, Natural (drug effects, immunology)
• Lymphocyte Activation (drug effects)
• Melanoma, Experimental
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Quinolines (agonists)
• Quinolones (pharmacology)
• Receptors, Aryl Hydrocarbon (agonists)
• Receptors, Virus (immunology)