Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress

Lindqvist, Daniel; Wolkowitz, Owen M.; Mellon, Synthia H.; Yehuda, Rachel; Flory, Janine D.; Henn‐Haase, Clare; Bierer, Linda M.; Abu‐Amara, Duna; Coy, Michelle; Neylan, Thomas C.; Makotkine, Iouri; Reus, Victor I.; Yan, Xiaodan; Taylor, Nicole; Marmar, Charles R.; Dhabhar, Firdaus S.

doi:10.1016/j.bbi.2014.06.003

Cited by 188 publications

(149 citation statements)

References 68 publications

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“…45 Moreover, increased plasma levels of pro-inflammatory cytokines, upregulated targets of NF-κB/Rel transcription factors 46 and molecular indicators of enhanced inflammation have been linked to PTSD vulnerability, 47 and to comorbid somatic diseases in childhood-abuse 48 and combat-related PTSD. 49 Here observation of prolonged inflammation and inhibited methylation of promoter regions for pro-inflammatory molecules are also consistent with multiple reports that show a correlation between stress-induced inflammation and chronic pain in PTSD. 40,[50][51][52][53] Stress-induced chronic inflammation is also implicated in chronic pain, [53][54][55] which may be responsible for the physical complaints possibly contributing to the impaired social and emotional functions of PTSD patients.…”

Section: Discussionsupporting

confidence: 76%

220. Molecular Indicators of Stress-Induced Neuroinflammation in a Mouse Model Simulating Features of Post-Traumatic Stress Disorder

Muhie

Gautam

Chakraborty

et al. 2017

Biological Psychiatry

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Section: Discussionsupporting

confidence: 76%

220. Molecular Indicators of Stress-Induced Neuroinflammation in a Mouse Model Simulating Features of Post-Traumatic Stress Disorder

Muhie

Gautam

Chakraborty

et al. 2017

Biological Psychiatry

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“…Furthermore, elevated CRP is also associated with impaired inhibition of fear-potentiated startle in the presence of a safety signal, a well-characterized biomarker of PTSD (Jovanovic et al, 2012). Combining concentrations of IL-1β, IL-6, TNF-α, IFN-γ, and CRP into a single pro-inflammatory score also indicated that inflammation is elevated in PTSD (Lindqvist et al, 2014b).…”

Section: Ptsd and Inflammationmentioning

confidence: 94%

Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

Michopoulos

Powers

Gillespie

et al. 2016

Neuropsychopharmacol

544

376

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The study of inflammation in fear-and anxiety-based disorders has gained interest as growing literature indicates that proinflammatory markers can directly modulate affective behavior. Indeed, heightened concentrations of inflammatory signals, including cytokines and C-reactive protein, have been described in posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), and phobias (agoraphobia, social phobia, etc.). However, not all reports indicate a positive association between inflammation and fear-and anxiety-based symptoms, suggesting that other factors are important in future assessments of inflammation's role in the maintenance of these disorders (ie, sex, co-morbid conditions, types of trauma exposure, and behavioral sources of inflammation). The most parsimonious explanation of increased inflammation in PTSD, GAD, PD, and phobias is via the activation of the stress response and central and peripheral immune cells to release cytokines. Dysregulation of the stress axis in the face of increased sympathetic tone and decreased parasympathetic activity characteristic of anxiety disorders could further augment inflammation and contribute to increased symptoms by having direct effects on brain regions critical for the regulation of fear and anxiety (such as the prefrontal cortex, insula, amygdala, and hippocampus). Taken together, the available data suggest that targeting inflammation may serve as a potential therapeutic target for treating these fear-and anxiety-based disorders in the future. However, the field must continue to characterize the specific role pro-inflammatory signaling in the maintenance of these unique psychiatric conditions.

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“…The current literature provides accruing evidence for excessive peripheral inflammation in PTSD. Evaluation of basal or stimulated peripheral cytokines (Maes et al, 1999;Spivak et al, 1997;Wong et al, 2000;Bob et al, 2010;Gill et al, 2010;Hoge et al, 2009;Symes et al, 2010;Tucker et al, 2010;von Känel et al, 2010;Lindqvist et al, 2014;Tursich et al, 2014;Plantinga et al, 2013) indicates there are abnormally increased concentrations of proinflammatory cytokines in patients with PTSD in most, but not all studies (de Kloet et al, 2007;Miller et al, 2001;Song et al, 1999). Few studies have examined cytokine levels in the CSF of individuals with PTSD.…”

Section: Inflammation and Ptsdmentioning

confidence: 99%

“…Of those, one reported higher concentrations of CSF IL-6 in combat veterans with PTSD (Baker et al, 2001), whereas the other reported no difference in CSF IL-6 concentrations in civilians with PTSD (Bonne et al, 2011). Cytokines may contribute to the pathophysiology of PTSD through a number of mechanisms that are independent of co-morbid depression and physical illnesses (Lindqvist et al, 2014;Tursich et al, 2014;Plantinga et al, 2013). Recently published gene expression studies show accumulating evidence of innate immune dysregulation in PTSD, and that this malfunctioning may be a risk factor for development of the disorder (Breen et al, 2015;Glatt et al, 2013;Tylee et al, 2015;Guardado et al, 2016).…”

Section: Inflammation and Ptsdmentioning

confidence: 99%

Posttraumatic stress disorder influences the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans

Lerman

Davis

Bertram

et al. 2016

Psychoneuroendocrinology

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a b s t r a c tObjective: Although posttraumatic stress disorder (PTSD) and chronic pain frequently occur in tandem, the pathophysiological mechanisms mediating this comorbidity are poorly understood. Because excessive inflammation occurs in both conditions, we examined the cerebrospinal fluid (CSF) concentrations of inflammatory response mediators interleukin 1-beta (IL-1␤), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF␣) and interleukin 10 (IL-10) after prolonged suprathreshold pain stimulus in 21 male combat veterans; 10 with PTSD and 11 combat controls (CC). Methods: After completing baseline quantitative sensory testing (QST) and psychological profiling, all patients received an injection of capsaicin into the quadriceps muscle. Spontaneously reported pain was measured for 30 min after the capsaicin injection. The evoked pain measure of temporal summation was tested between 70 and 110 min post capsaicin injection. Inflammatory (IL-1␤, IL-6, IL-8 TNF␣) and antiinflammatory (IL-10) CSF cytokines were measured before (baseline) and after capsaicin injection over a time frame of 110 min. Results: Following intramuscular capsaicin injection, pro-inflammatory cytokines [TNF␣, IL-6, IL-8] significantly increased (percent rise from baseline) in both groups, whereas IL-1␤ significantly increased in the PTSD group only. The anti-inflammatory cytokine IL-10 showed an immediate (within 10 min) increase in the CC group; however, the IL-10 increase in the PTSD group was delayed and not consistently elevated until 70 min post injection. Conclusion: These findings show significant central nervous system (CNS) differences in the inflammatory response to a deep pain stimulus in combat veterans with and without PTSD. They support the concept that abnormally elevated neuroinflammatory response to pain stimuli may be one CNS mechanism accounting for the high co-occurrence of PTSD and pain.Published by Elsevier Ltd.

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Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress

Cited by 188 publications

References 68 publications

220. Molecular Indicators of Stress-Induced Neuroinflammation in a Mouse Model Simulating Features of Post-Traumatic Stress Disorder

220. Molecular Indicators of Stress-Induced Neuroinflammation in a Mouse Model Simulating Features of Post-Traumatic Stress Disorder

Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

Posttraumatic stress disorder influences the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans

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