Brain-Spleen Inflammatory Coupling: A Literature Review

Abstract

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.

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

“…However, at 16 weeks we were surprised to find significantly decreased uptake in the spleens of male CKO mice while PCR confirmed no loss of NCB5OR in the spleen (data not shown). Direct communication and regulation from brain to the spleen moderated by cholinergic innervation has been identified and may contribute to this observation, and there is significant evidence demonstrating the existence of ‘brain-spleen inflammatory coupling’ (For review see (45)). Histological analysis of iron staining in the cerebellum revealed further evidence of an altered homeostatic state in 16-week-old CKO mice.…”

Acute splenic responses in patients with ischemic stroke and intracerebral hemorrhage

“…4 These include a reduction in number and apoptotic cell death of splenocytes, changes in cellularity and phenotype of splenocytes, and splenic atrophy. 6,[10][11][12][13][14]16,25 The translation of these findings in stroke patients remain challenging, and require a careful estimation of pre-stroke spleen volume as well as other contributory and confounding clinical factors.…”

“…Recent pre-clinical studies have focused on characterizing post-stroke splenic responses, and have highlighted the spleen's role in mediating peripheral immune system related secondary brain injury. 4 Multiple mechanisms of post-stroke splenic activation have been described in the literature which include, activation of sympathetic nervous system, 5,6 production of chemotactic cytokines, 7 and antigen presentation by the damaged brain. 8,9 Once activated, the spleen contracts in size, 10,11 undergoes cellular changes, cytokines.…”

Increased Risk of Hemorrhagic and Ischemic Strokes in Patients With Splenic Injury and Splenectomy

“…In addition to the aforementioned factors, bidirectional interaction between brain injury and spleen is proposed. 24 , 25 Brain injury, including trauma, hemorrhage, and ischemia, induces an immunoinflammatory response and release of inflammatory cytokines by macrophages in the spleen, the so-called “brain-spleen inflammatory coupling.” 24 , 25 The brain is susceptible to inflammatory substances activated by the immune-inflammatory processes. 26 For example, tumor necrosis factor (TNF)-α has been shown to result in exacerbation of brain ischemia.…”