Brain-immune communication pathways

Abstract

Communication between the central nervous and immune systems lies at the heart of the neuroimmune axis. We trace here some of the major conceptual hurtles which were raised, first against the acceptance of a neuroimmune axis and later in understanding it. We review the major concepts formulated and established during the last two decades and focus on four pathways that have been proposed as important in communication: the neural route, circumventricular organs, blood–brain barrier transport of cytokines, and secretions from BBB cells. These and other pathways have established the existence of a neuroimmune axis, but raise new questions on how they act and interact with one another.

Introduction

The concept that the brain and immune systems communicate lies at the heart of neuroimmunology. Indeed, the current power and future hope of this field lies in the strength it derives from the realization that the three great systems, the nervous, the endocrine, and the immune, by which the body communicates and regulates also communicate with one another. The last 20 years has witnessed the birth and the transformation of the field of neuroimmune communication. Of course, neuroimmunology existed long before that. But early neuroimmunologists generally treated the immune and the nervous systems as separate entities. Only disease conditions involving infection or immunological pathology within the nervous system were studied. These conditions were considered as a consequence of a breach of the insulation that isolated these two systems, thereby pathological in nature.

The concept that neuroimmune communication as an integrated part of a physiological supra-system that included both the immune and the nervous system distinguished the new neuroimmunology from its predecessor. This novel perspective met with considerable resistance and skepticism from its parent fields of neuroscience and immunology. For many traditional immunologists, meddling with the intricately organized immunological processes by the whim of neurotransmitters and neuropeptides seemed counterintuitive and an unneeded level of complexity. For the neuroscience of the time, the immune system also seemed an unlikely target to regulate. The nervous system was characterized by a speed of communication through a hardwired network of immobile neurons, whereas immune cells were built to move and roam, engulf pathogens and secret antibodies. For the nervous system to receive input from immune cells, one had to envision nerve terminals “synapsed” onto the mobile immune cells. This was certainly heresy at the time. In addition, most of the known immunological activities could be demonstrated in vitro without the help of neurons. Therefore, the need for the nervous system to respond to signals from the immune system was not obvious. The progress made in the field of neuroimmune communication has certainly cleared these hurdles to establish that these two systems do crosstalk extensively via multiple pathways. Such communication is not accidental, but plays significant physiological roles in optimizing the function of both systems and indeed the health of the entire organism.

We have chosen to examine four of the mechanisms by which these systems interact. As Fig. 1 and Table 1 illustrates, these areas have seen a substantial increase in interest as indicated by the number of publications in related fields. Although not inclusive, they together constitute much of the history of neuroimmunology and track very different courses in their developments, struggles for acceptance, and current applications to biological problems (Fig. 2).