GABAergic signaling in human and murine NK cells upon challenge with Toxoplasma gondii

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Amol K. Bhandage¹  Laura M. Friedrich¹  Sachie Kanatani¹  Simon Jakobsson-Björkén²  J. Ignacio Escrig-Larena²  Arnika K. Wagner³  Benedict J. Chambers²  Antonio Barragan¹ 

[1] Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University;Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital;Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital

关键词: Apicomplexa;    cell migration;    GABA-A receptor;    Host-pathogen;    immunomodulation;    Lymphocyte;    neurotransmitter;   

DOI  :  10.1002/JLB.3HI0720-431R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Protective cytotoxic and proinflammatory cytokine responses by NK cells impact the outcome of infections by Toxoplasma gondii , a common parasite in humans and other vertebrates. However, T. gondii can also sequester within NK cells and downmodulate their effector functions. Recently, the implication of GABA signaling in infection and inflammation-related responses of mononuclear phagocytes and T cells has become evident. Yet, the role of GABAergic signaling in NK cells has remained unknown. Here, we report that human and murine NK cells synthesize and secrete GABA in response to infection challenge. Parasitized NK cells secreted GABA, whereas activation stimuli, such as IL-12/IL-18 or parasite lysates, failed to induce GABA secretion. GABA secretion by NK cells was associated to a transcriptional up-regulation of GABA synthesis enzymes (glutamate decarboxylases [GAD65/67]) and was abrogated by GAD inhibition. Further, NK cells expressed GABA-A receptor subunits and GABA signaling regulators, with transcriptional modulations taking place upon challenge with T. gondii . Exogenous GABA and GABA-containing supernatants from parasitized dendritic cells (DCs) impacted NK cell function by reducing the degranulation and cytotoxicity of NK cells. Conversely, GABA-containing supernatants from NK cells enhanced the migratory responses of parasitized DCs. This enhanced DC migration was abolished by GABA-A receptor antagonism or GAD inhibition and was reconstituted by exogenous GABA. Jointly, the data show that NK cells are GABAergic cells and that GABA hampers NK cell cytotoxicity in vitro. We hypothesize that GABA secreted by parasitized immune cells modulates the immune responses to T. gondii infection.

【 授权许可】

CC BY