Modulation of immune function by glutamatergic neurons in the cerebellar interposed nucleus via hypothalamic and sympathetic pathways

Abstract

Our recent work has shown that the cerebellar interposed nucleus (IN) contains glutamatergic neurons that send axons directly to the hypothalamus. In the present study, we aimed to demonstrate modulation of cellular and humoral immunity by glutamatergic neurons in the cerebellar IN by means of gene interventions of glutaminase (GLS), an enzyme for glutamate synthesis, and to reveal pathways transmitting the immunomodulation. Injection of GLS-shRNA lentiviral vector into bilateral cerebellar IN downregulated GLS expression in the IN. The silencing of GLS gene in the cerebellar IN decreased interleukin (IL)-2 and interferon (IFN)-γ production, B-cell number, and IgM antibody level in response to antigen bovine serum albumin (BSA). On the contrary, injection of GLS lentiviral vector into bilateral cerebellar IN upregulated GLS expression in the IN. The GLS gene overexpression in the IN caused opposite immune effects to the GLS gene knockdown. Simultaneously, the GLS gene silencing in the cerebellar IN reduced and the GLS overexpression elevated glutamate content in the hypothalamus, but they both did not affect glycine and GABA contents in the hypothalamus. In addition, the immune changes caused by the GLS gene interventions in the IN were accompanied by alteration in norepinephrine content in the spleen and mesenteric lymph nodes but not by changes in adrenocortical and thyroid hormone levels in serum. These findings indicate that glutamatergic neurons in the cerebellar IN regulate cellular and humoral immune responses and suggest that such immunoregulation may be conveyed by cerebellar IN-hypothalamic glutamatergic projections and sympathetic nerves that innervate lymphoid tissues.