Recent evidence suggests a link between brain injury and the autonomic release of proinflammatory cytokines by resident macrophages in the spleen. This phenomenon, termed "brainspleen inflammatory coupling," has garnered attention from scientific and medical communities interested in developing novel treatments for traumatic brain injury (TBI). Cholinergic stimulation of the α7-subunit nicotinic acetylcholine receptor (α7NAchR) on splenic macrophages has been shown to inhibit their release of pro-inflammatory cytokines. This inhibition, mediated by the parasympathetic nervous system, has been shown to improve outcomes in animal models of sepsis, stroke, and TBI. As evidence of a beneficial role of splenic inhibition grows, new treatment strategies might be applied to many medical conditions involving neuroinflammation, a process that contributes to further neurological deterioration.Located within the peritoneal cavity, the spleen monitors the circulation and removes foreign material in the blood that potentially threatens homeostasis. As the primary mediator of the mononuclear phagocyte system, splenic leukocytes in the red and white pulp prevent devastating infections by encapsulated bacteria and intracellular pathogens. It comes as a surprise, then, that the same organ that plays such a crucial role in preventing infection may simultaneously exacerbate the inflammatory response after brain injury. With this in mind, a fresh body of evidence has suggested a link between brain injury and the autonomic release of inflammatory cytokines by macrophages in the spleen (Figure 1). This phenomenon, termed "brain-spleen inflammatory coupling," has garnered attention from scientific and medical communities seeking new treatments for ischemic and traumatic brain injuries.Physicians and scientists readily acknowledge that the intricate mechanisms driving acute inflammation remain a mystery. Dr. Niels Jerne, a Nobel Prize-winning immunologist, once described the immune system as a network of interacting cells and antibodies, analogous to the communication among neurons, glia, and their neurotransmitters in the central nervous system (CNS) (Jerne, 1985). For decades, these systems were thought to function independently; however, scientists have discovered several physiologic processes linking them. In the 1980s, Damjanovich and colleagues discovered that lymphocytes possess excitable membranes that behave similarly to those of neurons (Damjanovich et al., 1989). Leukocytes have also been shown to express β2-adrenergic receptors, indicating they are sensitive to changes in autonomic output (Bruynzeel, 1984). These findings provided the framework for the development of theories describing neurotransmitter control of inflammation and the link between emotional states and immune status.
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