GABAergic signaling in human and murine NK cells upon challenge withToxoplasma gondii

Abstract

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.

GABAergic signaling by cells of the immune system: more the rule than the exception

“…Importantly, in an infection challenge model, GABAergic activation in NK cells impacted their effector functions and interactions with DCs [54]. Upon challenge with T. gondii, NK cells responded with GABA secretion.…”

“…A recent report established that both human and mouse NK cells synthesize and secrete GABA, and express a GABAergic signaling machinery [54]. This includes GABA synthesis and degradation enzymes, GABA transporters, GABA-A R subunits, and CCCs, which can regulate GABA signaling (Table 1).…”

“…GABA modulates cytokine release by peripheral blood mononuclear cells and T cells [50], and T-cell cytotoxicity [123], but its effects on NKcell function have remained unclear [124]. Hypothetically, GABA may exert dual effects upon infection and inflammation: down-modulate pro-inflammatory responses and enhance DC migration [54]. In the context of infection in tissues, this dual effect may dampen inflammation but also modulate NK-DC interactions.…”

Crosstalk Between GABAergic Neurotransmission and Inflammatory Cascades in the Post-ischemic Brain: Relevance for Stroke Recovery

“…NK cells represent a population of innate immune cells accounting for about 5%–20% of human blood (Perera Molligoda Arachchige, 2021 ). Recently, this population has been defined as GABAergic cells due to the release of the neurotransmitter upon stimulation/exposure to pathogens and/or inflammatory stimuli (Bhandage et al, 2021 ). This would predestine NK cells’ interaction with other immune cells and brain resident GABAceptive cells.…”

“…This would predestine NK cells’ interaction with other immune cells and brain resident GABAceptive cells. One possible GABA-driven interaction comes from experiments performed in NK cells and dendritic cells infected with Toxoplasma gondii (Bhandage et al, 2021 ). Here, stimulation with exogenous GABA reduced degranulation and cytotoxicity of NK cells.…”