Nitric oxide in neuroimmune feedback signaling

Abstract

Abstract The gaseous neurotransmitter, nitric oxide (NO), has been implicated in regulation of the hypothalamo-pituitary-adrenal (HPA) axis. NO donors attenuate lipopolysaccharide (LPS)-induced release of corticotropin releasing factor (CRF) in vitro and NO synthase (NOS) inhibitors potentiate and prolong activation of the HPA axis by LPS in vivo. Changes in activities of the NO synthase isoforms, neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), have been reported in response to immune challenge. High doses of LPS administered either intravenously or intraperitoneally lead to increased activity of iNOS in perivascular microglia and in endothelial cells of microvascular origin. The NO produced by iNOS may in turn stimulate release of pro-inflammatory cytokines from cells of the brain. At much lower doses of endotoxin, however, where septic shock is not induced nor is the blood-brain barrier disrupted, nNOS and/or eNOS may play more important roles in NO production and signaling. Our work has shown that, in rats receiving 100 μg/kg intravenous LPS, blockade of NO production in the brain leads to elimination of the drop in body temperature and increased neuronal activation (including NO-producing neurons) in the paraventricular nucleus of the hypothalamus (PVN). The location of activated neurons in functionally distinct subdivisions of the PVN suggests that NO is involved in inhibition of the HPA axis, of sympathetic output, and of vasopressin-and/or oxytocin-producing neurons in response to LPS. We also found that inhibition of NO production leads to increased gene expression of the cytokine, interleukin-1 α (IL-1 α), in non-neuronal cells of the PVN 4 hours after LPS injection and a return to baseline levels at 8 hours. While IL-1 α affects secretion of corticotropin releasing factor (CRF) from the PVN, the mechanism is controversial since neither IL-1 α receptors nor IL-1 α binding have been reported in the PVN. NO's inhibition of IL-1 α gene expression may, therefore, be mediated through an intermediate molecule (e.g. prostaglandins, cytokines, NO). Using inhibitors of the NOS isoforms, we provide evidence that eNOS is the isoform responsible for the effects described above. While it is most likely that eNOS found in the vasculature of the brain is responsible for these effects, other possible sources include neurons or glial cells because eNOS has been shown to be present in hippocampal neurons and in astrocytes activated by cytokines. In conclusion, NO is a strong messenger candidate as a mediator of signaling between the immune system and the brain, both in septic and non-septic conditions. Our data suggest that NO from eNOS inhibits neuronal activation and IL-1 α gene expression in the PVN and affects temperature regulation in response to relatively mild levels of immune stress.