Glutamate augments retrovirus-induced immunodeficiency through chronic stimulation of the hypothalamic-pituitary- adrenal axis.

The mechanisms for activating the hypothalamic-pituitary-adrenal (HPA) axis and the roles glucocorticoids play in the pathogenesis of chronic infectious disease are largely undefined. Using the LP-BM5 model of retrovirus-induced immunodeficiency, we found alterations in HPA axis function, manifested as an increase in circulating levels of adrenocorticotropic hormone and corticosterone, beginning after only 3 mo of infection. These changes occurred contemporaneously with a shift in the profile of circulating cytokines from a Th1-dominant (IFN-gamma) to Th2-dominant (IL-4, IL-10) phenotype. No significant changes in either circulating IL-1beta, IL-6, or TNF-alpha levels were observed in infected mice. Administering the N-methyl-D-aspartate receptor antagonist MK-801 to infected mice normalized plasma adrenocorticotropic hormone and corticosterone levels, indicating that glutamate was a major activator of the HPA axis. Moreover, MK-801 treatment of late-stage mice also reversed the type 1 to type 2 cytokine shift to a degree comparable or superior to treatment with the glucocorticoid receptor antagonist RU-486. These findings indicate that HPA axis activation during LP-BM5 retrovirus infection is mediated by the chronic hyperactivation of glutamatergic pathways in the hypothalamus. Through this mechanism, the degree of peripheral immunodeficiency observed in the late-stage disease is profoundly augmented.

Temporal and spatial changes of quinolinic acid immunoreactivity in the immune system of lipopolysaccharide-stimulated mice.

Quinolinic acid (Quin), a metabolite of tryptophan, is a neurotoxin that has been implicated in a variety of neuropathologic disorders that have immune components. The goal of this study was to characterize the changes in the cellular localization of Quin immunoreactivity in a paradigm of immune stimulation with lipopolysaccharide (LPS) in vivo to provide a basis for further studies on the physiological role of Quin in the immune system. Intraperitoneal LPS injection significantly increased Quin immunoreactivity (IR) in lymphoid tissues within 24 h. Spatial changes in splenic Quin-IR demonstrated a shift from the periarterial lymphoid sheaths to the follicles before returning to control levels by 72 h post-LPS. The strongly Quin-IR cells were tentatively identified as interdigitating dendritic cells and macrophages. Only minimal Quin-IR was detected in liver and lung, even under conditions of LPS stimulation combined with tryptophan loading. These data emphasize the temporally and spatially specific nature of Quin-IR changes in lymphoid tissues under conditions of immune stimulation and raise the possibility that Quin may have an immunomodulatory function.