Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 to evade the pro-inflammatory NFκB pathway (original) (raw)
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Dysregulation of inflammation, neurobiology, and cognitive function in PTSD: an integrative review
Cognitive, Affective, & Behavioral Neuroscience
Compelling evidence from animal and human research suggest a strong link between inflammation and posttraumatic stress disorder (PTSD). Furthermore, recent findings support compromised neurocognitive function as a key feature of PTSD, particularly with deficits in attention and processing speed, executive function, and memory. These cognitive domains are supported by brain structures and neural pathways that are disrupted in PTSD and which are implicated in fear learning and extinction processes. The disruption of these supporting structures potentially results from their interaction with inflammation. Thus, the converging evidence supports a model of inflammatory dysregulation and cognitive dysfunction as combined mechanisms underpinning PTSD symptomatology. In this review, we summarize evidence of dysregulated inflammation in PTSD and further explore how the neurobiological underpinnings of PTSD, in the context of fear learning and extinction acquisition and recall, may interact with inflammation. We then present evidence for cognitive dysfunction in PTSD, highlighting findings from human work. Potential therapeutic approaches utilizing novel pharmacological and behavioral interventions that target inflammation and cognition also are discussed.
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2018
Pro-inflammatory cytokines, such as interleukin (IL)-1β, have been implicated as underlying pathophysiological mechanisms and potential biomarkers of post-traumatic stress disorder (PTSD). This systematic review examines data regarding IL-1β production/concentration in human and animal studies of PTSD. In accordance with PRISMA guidelines, relevant articles from PubMed were reviewed from inception until July 10, 2017. Nineteen studies were eligible for inclusion. Animal studies demonstrated increased hippocampal IL-1β in rodent models of PTSD. Several immunomodulatory drugs were shown to reduce elevated IL-1β levels and anxiety-like behaviors in animals. Human cross-sectional studies showed contradictory results; serum and plasma IL-1β concentrations in PTSD patients were either elevated or did not differ from control groups. In vitro IL-1β production by stimulated cells demonstrated no difference between PTSD and control participants, although spontaneous in vitro production of IL-...
Biological Psychiatry
A social-stress mouse model was used to simulate features of post-traumatic stress disorder (PTSD). The model involved exposure of an intruder (male C57BL/6) mouse to a resident aggressor (male SJL) mouse for 5 or 10 consecutive days. Transcriptome changes in brain regions (hippocampus, amygdala, medial prefrontal cortex and hemibrain), blood and spleen as well as epigenome changes in the hemibrain were assayed after 1-and 10-day intervals following the 5-day trauma or after 1-and 42-day intervals following the 10-day trauma. Analyses of differentially expressed genes (common among brain, blood and spleen) and differentially methylated promoter regions revealed that neurogenesis and synaptic plasticity pathways were activated during the early responses but were inhibited after the later post-trauma intervals. However, inflammatory pathways were activated throughout the observation periods, except in the amygdala in which they were inhibited only at the later post-trauma intervals. Phenotypically, inhibition of neurogenesis was corroborated by impaired Y-maze behavioral responses. Sustained neuroinflammation appears to drive the development and maintenance of behavioral manifestations of PTSD, potentially via its inhibitory effect on neurogenesis and synaptic plasticity. By contrast, peripheral inflammation seems to be directly responsible for tissue damage underpinning somatic comorbid pathologies. Identification of overlapping, differentially regulated genes and pathways between blood and brain suggests that blood could be a useful and accessible brain surrogate specimen for clinical translation.
Stress Increases Vulnerability to Inflammation in the Rat Prefrontal Cortex
Journal of Neuroscience, 2006
Inflammation could be involved in some neurodegenerative disorders that accompany signs of inflammation. However, because sensitivity to inflammation is not equal in all brain structures, a direct relationship is not clear. Our aim was to test whether some physiological circumstances, such as stress, could enhance susceptibility to inflammation in the prefrontal cortex (PFC), which shows a relative resistance to inflammation. PFC is important in many brain functions and is a target for some neurodegenerative diseases. We induced an inflammatory process by a single intracortical injection of 2 g of lipopolysaccharide (LPS), a potent proinflammogen, in nonstressed and stressed rats. We evaluated the effect of our treatment on inflammatory markers, neuronal populations, BDNF expression, and behavior of several mitogen-activated protein (MAP) kinases and the transcription factor cAMP response element-binding protein.
Journal of Neuroscience, 2014
Interleukin-1 (IL-1) is an inflammatory cytokine that plays a prominent role in stress-induced behavioral changes. In a model of repeated social defeat (RSD), elevated IL-1 expression in the brain was associated with recruitment of primed macrophages that were necessary for development of anxiety-like behavior. Moreover, microglia activation and anxiety-like behavior associated with RSD did not occur in IL-1 receptor type-1 knockout (IL-1R1 KO) mice. Therefore, the objective of this study was to examine the role of IL-1 signaling in RSD-induced macrophage trafficking to the brain and anxiety-like behavior. Initial studies revealed that RSD did not increase circulating myeloid cells in IL-1R1 KO mice, resulting in limited macrophage trafficking to the brain. In addition, IL-1R1 KO bone marrowchimera mice showed that IL-1R1 expression was essential for macrophage trafficking into the brain. To differentiate cellular mediators of stress-induced IL-1 signaling, endothelial-specific IL-1R1 knock-down (eIL-1R1kd) mice were used. Both wild-type (WT) and eIL-1R1kd mice had increased circulating monocytes, recruitment of macrophages to the brain, and altered microglia activation after RSD. Nonetheless, RSD-induced expression of IL-1, TNF-␣, and IL-6 mRNA in brain CD11b ϩ cells was attenuated in eIL-1R1kd mice compared with WT. Moreover, anxiety-like behavior did not develop in eIL-1R1kd mice. Collectively, these findings demonstrated that there was limited RSD-induced priming of myeloid cells in IL-1R1 KO mice and disrupted propagation of neuroinflammatory signals in the brain of eIL-1R1kd mice. Furthermore, these data showed that transduction of IL-1 signaling by endothelial cells potentiates stressinduced neuroinflammation and promotes anxiety-like behavior.
Brain, Behavior, and Immunity, 2013
Acute and chronic stressors sensitize or prime the neuroinflammatory response to a subsequent peripheral or central immunologic challenge. However, the neuroimmune process(es) by which stressors prime or sensitize subsequent neuroinflammatory responses remains unclear. Prior evidence suggested that toll-like receptors (TLRs) might be involved in the mediation of primed neuroinflammatory responses, but the role of TLRs during a stressor has never been directly tested. Here, a novel TLR2 and TLR4 antagonist, OxPAPC, was used to probe the contribution of TLRs in the stress sensitization phenomenon. OxPAPC has not previously been administered to the brain, and so its action in blocking TLR2 and TLR4 action in brain was first verified. Administration of OxPAPC into the CNS prior to stress prevented the stress-induced potentiation of hippocampal pro-inflammatory response to a subsequent peripheral LPS challenge occurring 24 h later. In addition, in vivo administration of OxPAPC prior to stress prevented the sensitized pro-inflammatory response from isolated microglia following administration of LPS ex vivo, further implicating microglia as a key neuroimmune substrate that mediates stress-induced sensitized neuroinflammation.
IL-1 is an essential mediator of the antineurogenic and anhedonic effects of stress
Proceedings of the National Academy of Sciences, 2008
Stress decreases neurogenesis in the adult hippocampus, and blockade of this effect is required for the actions of antidepressants in behavioral models of depression. However, the mechanisms underlying these effects of stress have not been identified. Here, we demonstrate an essential role for the proinflammatory cytokine IL-1β. Administration of IL-1β or acute stress suppressed hippocampal cell proliferation. Blockade of the IL-1β receptor, IL-1RI, by using either an inhibitor or IL-1RI null mice blocks the antineurogenic effect of stress and blocks the anhedonic behavior caused by chronic stress exposure. In vivo and in vitro studies demonstrate that hippocampal neural progenitor cells express IL-1RI and that activation of this receptor decreases cell proliferation via the nuclear factor-κB signaling pathway. These findings demonstrate that IL-1β is a critical mediator of the antineurogenic and depressive-like behavior caused by acute and chronic stress.
Exposure to Acute Stress Induces Brain Interleukin1b Protein in the Rat
1998
Peripheral immune stimulation such as that provided by lipopolysaccharide (LPS) has been reported to increase brain levels of IL-1 mRNA, immunoreactivity, and bioactivity. Stressors produce many of the same neural and endocrine responses as those that follow LPS, but the impact of stressors on brain interleukin-1 (IL-1) has not been systematically explored. An ELISA designed to detect IL-1 was used to measure levels of IL-1 protein in rat brain. Brain IL-1 was explored after exposure to inescapable shock (IS; 100 1.6 mA tail shocks for 5 sec each) and LPS (1 mg/kg) as a positive control. Rats were killed either immediately or 2, 7, 24, or 48 hr after IS. Brains were dissected into hypothalamus, hippocampus, cerebellum, posterior cortex, and nucleus tractus solitarius regions. LPS produced widespread increases in brain IL-1, but IS did not. Adrenal glucocorticoids are known to suppress IL-1 produc-tion in both the periphery and brain. Thus, it was possible that the stressor did provide stimulus input to the brain IL-1 system(s), but that the production of IL-1 protein was suppressed by the rapid and prolonged high levels of glucocorticoids produced by IS. To test this possibility rats were adrenalectomized or given sham surgery, with half of the adrenalectomized rats receiving corticosterone replacement to maintain basal corticosterone levels. IS produced large increases in brain IL-1 protein in the adrenalectomized subjects 2 hr after stress, whether basal corticosterone levels had been maintained. Thus elimination of the stress-induced rise in corticosterone unmasked a robust and widespread increase in brain IL-1.