The LHRH-astroglial network of signals as a model to study neuroimmune interactions: assessment of messenger systems and transduction mechanisms at cellular and molecular levels

Abstract

Neurons and astrocytes have a close anatomic and functional relationship that plays a crucial role during development and in the adult brain. Astrocytes in the central nervous system (CNS) express receptors for a variety of growth factors (GFs), neurotransmitters and/or neuromodulators; in turn, neuronal cells can respond to astrocyte-derived GFs and control astrocyte function via a common set of signaling molecules and intracellular transducing pathways. There is also increasing evidence that soluble factors from lymphoid/mononuclear cells are able to modulate the growth and function of cells found in the CNS, specifically macroglial and microglial cells. Furthermore, glial cells can secrete immunoregulatory molecules that influence immune cells as well as the glial cells themselves. As neuronal and immune cells share common signaling systems, the potential exists for bidirectional communication not only between lymphoid and glial cells, but also between neuronal cells and immune and glial cells. In the present work, interactions of luteinizing-hormone-releasing hormone (LHRH) and the astroglial cell are proposed as a prototype for the study of neuroimmune communication within the CNS in the light of (1) the commonality of signal molecules (hormones, neurotransmitters and cytokines) and transduction mechanisms shared by glia LHRH neurons and lymphoid cells; (2) the central role of glia in the developmental organization and pattern of LHRH neuronal migration during embryogenesis, and (3) the strong modulatory role played by sex steroids in mechanisms involved in synaptic and interneuronal organization, as well as in the sexual dimorphisms of neuroendocrine-immune functions. During their maturation and differentiation in vitro, astroglial cells release factors able to accelerate markedly the LHRH neuronal phenotypic differentiation as well as the acquisition of mature LHRH secretory potential, with a potency depending on both the 'age' and the specific brain localization of the astroglia, as well as the degree of LHRH neuronal differentiation in vitro. Regional differences in astroglial sensitivity to estrogens were also measured. Different experimental paradigms such as coculture and mixed-culture models between the immortalized LHRH (GT1-1) neuronal cell line and astroglial cells in primary culture, disclosed the presence of a bidirectional flow of informational molecules regulating both proliferative and secretory capacities of each cell type. The importance of adhesive mechanisms in such cross-talk is underscored by the complete abolition of GT1-1 LHRH production and cell proliferation following the counteraction of neuronal-neuronal/neuronal-glial interactions through addition of neural-cell adhesion molecule antiserum. Other information came from pharmacological experiments manipulating the astroglia-derived cytokines and/or nitric oxide, which revealed cross-talk between the neuronal and astroglial compartments. From the bulk of this information, it seems likely that interactions between astroglia and LHRH neurons play a major role in the integration of the multiplicity of brain signals converging on the LHRH neurons that govern reproduction. Another important facet of neuronal-glial interactions is that concerning neuron-guided migration, and unraveling astroglial/LHRH-neuronal networks might then constitute an additional effort in the comprehension of defective LHRH-neuronal migration in Kallman's syndrome.