I. INTRODUCTION
Our understanding of physiology has benefited greatly from the advances in molecular biology that have been at the origin of the explosive development of genetics and -omic techniques. What used to be a rarity a few decades ago, studying the expression and function of a given molecule within a different physiological system from the one in which it was first identified, has now become the norm.
Communication signals and signaling pathways are commonly studied in different physiological systems using the same tools. This is the case, for instance, for purinergic signaling, which is investigated by immunologists for its role in macrophage function and plasticity (57) and by neurobiologists for its regulatory activity on synaptic plasticity (203). Blurring of the boundaries between disciplines is probably the main outcome of this wave of research. However, this situation is still relatively new, and the transition to it has been very progressive.
This is well reflected in the history of the research efforts in neural–immune interactions (TABLE 1) (1). What was initially of interest to only a few practitioners in psychosomatic medicine—the influence of personality factors and emotional states on sensitivity to disease, or more generally the interrelationships among mind, body, and environment in health and disease— became an object of scientific investigation in the 1950s, when it was brought into the laboratory to be subjected to a reductionist approach (139).
Not surprisingly, retrospectively, but at the time difficult for hardcore pathologists to admit, biobehavioral factors, in the form of exposure to well-defined stressors, were found to influence the initiation and progression of various infectious and noninfectious diseases in animal models of pathology.
Once it became possible to assess immune functions in a routine manner using techniques borrowed from clinical immunology, these influences were ascribed to modulation of immune responses by activation of the stress pathways. The predominant stress pathways that were investigated were the hypothalamicpituitary-adrenal (HPA) axis, the activation of which results in the release of cortisol or corticosterone (depending on the species), and the sympathetic nervous system, the activation of which results in the release of epinephrine and norepinephrine.
The study of psychological modulation of immunity, initially conducted at Institut Pasteur in Paris, France in the 1920s using Pavlovian conditioned stimuli (157), was revived in the 1970s by Ader and Cohen (2), who rediscovered the phenomenon of conditioned immunosuppression. Working at the University of Rochester Medical Center, they showed that it is possible to increase the immunosuppressive effect of cyclophosphamide by presenting rats with the taste of a saccharin solution previously paired with exposure to the poisonous side effects of cyclophosphamide (2). These were key experiments that indirectly revealed the existence of an intricate network of bidirectional communications between the central nervous and the immune systems. Such communication pathways had been suspected before but not yet demonstrated. Therefore, they were not amenable to mechanistic analysis.
The field of research that studies the basic aspects of neural– immune interactions was variously labeled neuroimmunomodulation, neuroimmunoendocrinology, or psychoneuroimmunology, depending on which scientific discipline predominated at the time. However, this new wave of interdisciplinary research gained momentum in the scientific community at large only when the pathways of communication between the nervous system and the immune system were elucidated. In a nonconcerted effort, neuroanatomists demonstrated the existence of a sympathetic innervation of primary and secondary lymphoid organs (71), neuroendocrinologists described the expression and function of neuroendocrine receptors on immune cells (95, 177), and cell biologists showed that activated immunocytes express and release molecular factors previously identified in the neuroendocrine system, such as adrenocorticotrophin, which is processed from proopiomelanocortin in lymphocytes in the same manner as in the anterior pituitary (212, 213). The emphasis on brain-to-immune, rather than immune-to-brain, communication pathways was mainly due to the active involvement of neuroendocrinologists in the field and to the progress made in the elucidation of the chemical nature and receptor mechanisms of most neuroendocrine factors (93).
Although the existence of an immune-to-brain communication pathway had been inferred by Besedovsky et al. (17), whose elegant physiological studies demonstrated activation of the HPA axis and the sympathetic nervous system during the peak antibody response in mice vaccinated with a T-cell antigen, the molecular nature of this communication pathway took longer to be elucidated. Cloning and recombinant expression of cytokines, the autocrine and paracrine communication factors between immune cells, did not take place before the early 1980s (60). The ability of the first cloned cytokine interleukin (IL)-1 to activate the HPA axis and induce some of the physiological changes observed in a mouse model of antibody response to sheep red blood cells was reported in 1986, shortly after the demonstration of the pyrogenic activity of this cytokine (16).
As previously presented in Physiological Reviews, basic communication mechanisms between the nervous and immune systems include the immune production and function of neuroendocrine peptide hormones (22), the effects of neuroendocrine hormones on the immune system and the innervation of lymphoid organs by the sympathetic nervous system (142), and the regulatory effects of cytokines on the HPA axis (232). The objective of this review is not to update this information but to introduce a new perspective: the fascinating complementarity between short-range and long range communication mechanisms between the nervous and the immune systems.
Studies of long-range communication mechanisms were initially favored, certainly because of the strong predominance of neuroendocrinology and neuroanatomy in the emerging field of psychoneuroimmunology. Communication from the nervous system to the immune system was believed to take place exclusively via circulating hormones produced by the neuroendocrine system (e.g., cortisol, but also growth hormone and prolactin) and via neurotransmitters (e.g., epinephrine and norepinephrine) released in the vicinity of immune cells by nerve endings in primary and secondary lymphoid organs. However, the discovery that immune cells can themselves produce and release neuroendocrine factors and neuromediators led to a shift in interest from long-range to short-range communication pathways.
Similarly, communication from the immune system to the brain was initially seen as involving circulating immune factors acting indirectly on the brain via the formation of brain-penetrant molecules (prostaglandins) in brain areas where the blood-brain barrier is leaky, the so-called circumventricular organs. This was how endogenous pyrogens were perceived as being responsible for the development of the fever response to infectious pathogens. It took time for neurobiologists to realize that brain innate immune cells actually produce the same cytokines as those originally characterized as endogenous pyrogens and that these locally produced cytokines are responsible for the various components of the response of the host to infection. It took even longer to recognize that cytokines produced locally by brain cells are responsible for intricate functional and structural interactions between endothelial cells, glia, and neurons.