The interaction of the circadian and immune system: Desynchrony as a pathological outcome to traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a complex and costly worldwide phenomenon that can lead to many negative health outcomes including disrupted circadian function. There is a bidirectional relationship between the immune system and the circadian system, with mammalian coordination of physiological activities being controlled by the primary circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN receives light information from the external environment and in turn synchronizes rhythms throughout the brain and body. The SCN is capable of endogenous self-sustained oscillatory activity through an intricate clock gene negative feedback loop. Following TBI, the response of the immune system can become prolonged and pathophysiological. This detrimental response not only occurs in the brain, but also within the periphery, where a leaky blood brain barrier can permit further infiltration of immune and inflammatory factors. The prolonged and pathological immune response that follows TBI can have deleterious effects on clock gene cycling and circadian function not only in the SCN, but also in other rhythmic areas throughout the body. This could bring about a state of circadian desynchrony where different rhythmic structures are no longer working together to promote optimal physiological function. There are many parallels between the negative symptomology associated with circadian desynchrony and TBI. This review discusses the significant contributions of an immune-disrupted circadian system on the negative symptomology following TBI. The implications of TBI symptomology as a disorder of circadian desynchrony are discussed.

Circadian rhythm in systemic autoimmune conditions: Potential of chrono-immunology in clinical practice: A narrative review

“…CR genes regulate pathogen recognition and cytokine secretion. [17,18] Guerro-Vargas et al demonstrated the involvement of the SCN in the regulation of inflammatory responses. Mice with an absent SCN exhibited an extreme and lethal proinflammatory response to stimuli.…”

Efficacy and acceptability of blue-wavelength light therapy for post-TBI behavioral symptoms: A systematic review and meta-analysis of randomized controlled trials

“…TBI-induced circadian disruption may be caused by many brain functions, e.g., circadian hormone regulation and neurotransmitter functions [ 46 ]. Neuroinflammation due to brain injury may also initiate a prolonged immune response that changes the expression of clock genes in the SCN and circadian function [ 47 , 48 ]. Clinical findings suggest two common types of post-TBI circadian rhythm disorders, including delayed sleep phase syndrome and irregular sleep-wake patterns [ 49 ].…”

Future Perspectives in Spinal Cord Repair: Brain as Saviour? TSCI with Concurrent TBI: Pathophysiological Interaction and Impact on MSC Treatment

“…Similar to TBI patients, those with cervical spinal cord injury commonly develop sleep disorders that are accompanied by circadian disruptions like dysregulated circadian rhythm and course of melatonin production [ 223 , 224 ], core body temperature [ 225 ], and aberrant expression patterns of clock genes in peripheral blood mononuclear cells [ 226 ]. Sleep abnormalities have been shown to negatively affect the outcome of TBI [ 227 ], and a recent study in mice shows involvement of circadian regulation in the neuroinflammation and blood–spinal cord barrier disruption following TSCI [ 228 ]; therefore, different kinds of chronotherapeutics have already been clinically tested. Blue-wavelength light therapy seemed to be helpful for patients with mild TBI or long-term fatigue following TBI [ 229 , 230 ].…”

“…Melatonin preconditioning of these cells could improve their regenerative potential [ 298 , 299 , 300 ]. As TSCI and TBI both negatively affect circadian rhythm as well as circadian-mediated inflammatory and healing cascades [ 227 , 233 , 301 , 302 ], chronotherapeutic aspects in MSC therapy for TSCI should be considered.…”