Variable neuroendocrine–immune dysfunction in individuals with unfavorable outcome after severe traumatic brain injury
Introduction
The pathogenesis of traumatic brain injury (TBI) is a highly heterogeneous process. The wide variability associated with acute secondary injury mechanisms has led to significant challenges in discerning effective diagnostic and treatment modalities (Lowenstein, 2009, Faden, 2001). Therefore, recent research has begun to examine biomarker profiles to characterize unique injury responses (Jain, 2008). At present, research suggests that both inflammatory markers and hormones may serve as reliable indicators of acute injury pathology and outcome, findings that may eventually aid in the development of individualized treatment plans (Dash et al., 2010, Kochanek et al., 2008, Wagner et al., 2011, Santarsieri et al., 2014, Juengst et al., 2014).
A growing body of evidence suggests that neuroinflammation contributes to injury and repair after TBI, and thus, has both beneficial and detrimental effects (Morganti-Kossmann et al., 2002, Amor et al., 2009, Woodcock and Morganti-Kossman, 2013). Although the brain has long been considered immunologically privileged, new evidence suggests that the intrinsic immuno-regulatory properties of central nervous system (CNS) cells, as well as peripheral immune cells and molecules crossing the blood–brain barrier (BBB), influence the brain’s response to injury (Becher et al., 2000, Dardiotis et al., 2012). Additionally, cytokine trafficking may occur via receptor-mediated transcytosis or activation of afferent vagal fibers (Banks, 2005, Maier et al., 1998). The central component of the brain’s innate immune system is microglia. Activated microglia are largely indistinguishable from peripheral macrophages and can release numerous inflammatory mediators, including cytokines and adhesion molecules (Rivest, 2009, Gehrmann et al., 1995). Additionally, bone marrow-derived microglial precursors migrate into the CNS after injury (Hickey, 1999, Ransohoff et al., 2003). Leukocyte migration into brain parenchyma is facilitated by binding to endothelial selectins and adhesion molecules (Hurley et al., 2002, Rahman and Fazal, 2009). Depending on the extent, timing or location, the inflammatory response may be characterized as either neuroprotective or neurodegenerative (Morganti-Kossmann et al., 2002). For example, microglial activation is necessary for the clearance of apoptotic cells after injury and may facilitate injury-induced neural plasticity through various mechanisms, including BDNF signaling (Neumann et al., 2009, Parkhurst et al., 2013). However, chronic inflammation and sustained microglial activation have been linked to cytotoxicity and neurodegeneration (Bal-Price and Brown, 2001, Gentleman et al., 2004). Importantly, microglial activation, and associated inflammatory responses, can persist for years after TBI (Johnson et al., 2013, Ramlackhansingh et al., 2011).
Hypothalamic–pituitary–adrenal (HPA) axis activation after trauma and illness has been extensively studied (Munck et al., 1984, Desborough, 2000). Although increased cortisol secretion is a critical component of the body’s response to injury, continued activation or dysfunctional regulation of this pathway can lead to elevated CNS cortisol levels, which can have adverse effects on mood, cognition, and neuron survival (Sapolsky, 1992, Traskman et al., 1980, Pearson et al., 2010). Our prior research showed that elevated CSF, but not serum, cortisol during the first week post-TBI is associated with unfavorable outcomes, and BBB disruption and impaired efflux transporter mechanisms may contribute to harmful levels of cortisol in the CNS (Santarsieri et al., 2014). Additionally, diminished sensitivity of pituitary corticotropin releasing hormone (CRH) to glucocorticoids and/or diminished glucocorticoid receptor affinity may alter HPA negative feedback mechanisms that affect physiological cortisol production (Reincke et al., 1993, Van den Berghe et al., 1998). Conversely, relatively low cortisol levels in the face of critical illness, often labeled acute adrenal insufficiency (AI), has been linked to unfavorable outcomes as well (Van den Berghe et al., 1998, Marik and Zaloga, 2002). Various factors, including genetic variation, acute care treatments with drugs that impact the HPA axis, and the environment, may contribute to an individual’s unique systemic cortisol response (Jabbi et al., 2007, Kirschbaum et al., 1995, Mahon et al., 2013, Hildreth et al., 2008, Llompart-Pou et al., 2007) and its impact on CNS cortisol levels, a fact that highlights the need for research addressing individual variability in hormonal and immune responses after TBI.
Until recently, the immune system and neuroendocrine system were believed to function independently. However, a bi-directional relationship between the two systems is now well established (Reichlin, 1993, Maier, 2002). The HPA axis can be activated by endogenous and exogenous cytokines via multiple humoral and neural mechanisms (Besedovsky and del Rey, 2011, Turnbull and Rivier, 1999). For example, the pro-inflammatory cytokines like IL-1β, IL-6 and TNFα are considered potent activators of the HPA axis (Sapolsky et al., 1987, Mastorakos et al., 1993, Besedovsky et al., 1991, Turnbull and Rivier, 1995). Further, the traditional view that glucocorticoids have mainly anti-inflammatory properties has been challenged; cortisol regulation of inflammation is now recognized as both dualistic and dynamic (Yeager et al., 2011, Sapolsky et al., 2000, Munck and Naray-Fejes-Toth, 1994, Yeager et al., 2004). That is, cortisol can both promote and suppress inflammation, and these properties are dose-dependent and temporally dynamic. In the periphery, low or basal cortisol levels permissively allow up-regulation of the immune system and increased pro-inflammatory cytokine production (Munck et al., 1984, Yeager et al., 2011). When elevated, however, glucocorticoids have negative-feedback regulatory control that can shut down inflammatory cascades, thereby preventing accumulation of harmful levels of inflammatory markers (Sapolsky et al., 2000, Besedovsky and del Rey, 2000). Thus, it is high or chronic plasma cortisol levels, such as those associated with stress or pharmacological glucocorticoid administration, which are responsible for the hormone’s well-established anti-inflammatory or immunosuppressive properties. The balance of this intricate negative feedback mechanism is an integral part of a healthy immune response, as evidence suggests that dysfunction in this communication pathway may facilitate a chronic inflammatory state, as observed with rheumatic diseases (Silverman and Sternberg, 2012, Sternberg et al., 1989).
Interestingly, cortisol’s effects on the immune response in the injured brain differ significantly from its effects in the periphery. Studies, both in vivo and in cell culture, examining inflammatory cell extravasation and migration, inflammatory messenger levels, and transcription factor activation after glucocorticoid exposure have concluded that chronic glucocorticoid exposure is not uniformly anti-inflammatory in the injured CNS (for a thorough review, see Sorrells and Sapolsky, 2007). Our current understanding is that, in the CNS, basal or acute-stress glucocorticoid levels suppress inflammation, while chronic, high-dose glucocorticoid levels exacerbate it (Sorrells and Sapolsky, 2007). The concept is relatively novel and complicated by a variety of factors influencing glucocorticoid effects (e.g., brain region, cell type, synthetic vs. endogenous glucocorticoid, timing of administration, and dose) (Dinkel et al., 2002). Regardless, this literature underscores the need to revisit the classic model of glucocorticoids as having strictly anti-inflammatory effects, and to assess, in clinical populations, the effects of TBI on cortisol-inflammatory relationships.
We used a rehabilomics based framework (Wagner and Zitelli, 2013) to guide our research design; that is, we identified biomarker relationships informative to secondary injury mechanisms and outcome prognostication with a focus on how this information may help shape individualized treatment plans. We hypothesized that the initial inflammatory insult of a TBI triggers an HPA response, and that cortisol regulates the ongoing inflammatory response. Further, we hypothesized that dysfunctional neuroendocrine–immune communication could be defined through unique CSF cortisol and immune marker relationships associated with unfavorable outcome. Our goals were to (1) identify cerebrospinal fluid (CSF) inflammatory markers associated with outcome and cortisol physiology, and based on these criteria, create an inflammatory load score (ILS), (2) characterize the relationship between the immune and neuroendocrine systems after TBI and (3) determine if/how the neuroendocrine–immune relationship differs by both outcome and cortisol trajectory (TRAJ) in the setting of TBI.
Section snippets
Subjects
This prospective observational cohort study was approved by the Institutional Review Board at the University of Pittsburgh. Informed consent was provided by next-of-kin. When possible, subjects provided assent and/or were later reconsented if their cognitive and informed decision making capacity improved satisfactorily. Samples and data obtained in acute care were obtained as a part of a year-long study. Thus, if a surviving subject became cognitively able, self-consent was obtained during that
Description of the cohort
Table 1a, Table 1b outline the population characteristics by CSF cortisol TRAJ group membership, 6 month GOS, and ILS. The mean age of the cohort was 35.80 ± 1.73 years, with an age range of 16–73 years. Women represented 20% of the population. The primary mechanism of injury among both men and women was motor vehicle collisions (45%) followed by motorcycle collisions (21%). The median GCS score for the cohort was 7, and the mean ± SEM ISS score was 33.69 ± 0.88. The most common injury types observed on
Discussion
There exists compelling data regarding the dual role of neuroinflammation in the injured brain (Morganti-Kossmann et al., 2002, Woodcock and Morganti-Kossman, 2013) and also for the bi-directional communication between the immune and neuroendocrine systems (Reichlin, 1993, Maier, 2002, Chrousos, 1995). Thus, the aims of the present study were to (1) examine the interrelationships between cortisol and inflammatory markers after TBI and (2) determine if/how the nature of this relationship varied
Conflicts of interest
The authors report no actual or potential conflicts of interest.
Acknowledgments
This work was supported by DOD W81XWH-071-0701, CDC R49 CCR 323155, and NIH 5P01NS030318. The authors would like to thank the University of Pittsburgh Cancer Institute and their Luminex Facility for assay performance. Special thanks to Dr. Anna Lokshin and John Snyder for input on data scaling for inflammatory markers.
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- 1
University of Pittsburgh, Department of Physical Medicine & Rehabilitation, 3471 Fifth Ave, Suite 202, Pittsburgh, PA 15213, USA. Tel.: +1 412 648 6666; fax: +1 412 692 4354.
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University of Pittsburgh, Safar Center for Resuscitation Research, 3434 Fifth Ave, Pittsburgh, PA 15260, USA. Tel.: +1 412 624 6735; fax: +1 412 624 0943.
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Wake Forest Baptist Medical Center, Department of Obstetrics and Gynecology, Medical Center Boulevard, Winston-Salem, NC 27157-1021, USA. Tel.: +1 336 716 4594; fax: +1 336 716 5656.