Effects of IL1B single nucleotide polymorphisms on depressive and anxiety symptoms are determined by severity and type of life stress

Kovács, D; Eszlári, Nóra; Petschner, Péter; Pap, Dorottya; Vas, Szilvia; Kovács, Péter; Gonda, Xénia; Juhász, Gabriella; Bagdy, György

doi:10.1016/j.bbi.2016.02.012

Cited by 50 publications

(40 citation statements)

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“…Central administration of IL-1β produces several stress-like effects and pathological changes [12, 14–16]. Hippocampal tissue inflammation and, particularly, enhanced interleukin-1β (IL-1β) signaling may contribute to depression [17]. In contrast, blockade of the hippocampal IL-1β receptor, IL-1RI, abolishes the anhedonic behavioral effects of chronic unpredictable stress (CUS) [18, 19].…”

Section: Introductionmentioning

confidence: 99%

Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors

Yue

Huang

Zhu

et al. 2017

J Neuroinflammation

255

174

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BackgroundIn recent years, proinflammatory cytokine interleukin-1β (IL-1β) was considered to play a critical role in the pathogenesis of depression. In addition, P2X7 receptor (P2X7R), a member of the purinergic receptor family, which is predominantly present on microglia, as well as on astrocytes and neurons in lesser amounts in the central nervous system, was suggested to be involved in the processing and releasing of IL-1β. Here, we investigated the role of P2X7R in the pathogenesis of depression.MethodsMale Sprague-Dawley rats were subjected to chronic unpredictable stressors (CUS) for 3 weeks. At the end of week 1, 2, and 3, extracellular ATP, caspase 1, IL-1β, and components and activation of NLRP3 inflammasome (nucleotide-binding, leucine-rich repeat, pyrin domain containing 3) were evaluated as biomarker of neuroinflammation. In separate experiments, the rats were microinjected with P2X7R agonists ATP, BzATP, and saline into the hippocampus, respectively, or exposed to CUS combined with hippocampal microinjection with P2X7R antagonist, BBG and A438079, and saline, respectively, for 3 weeks, followed by exposed to forced swimming test and open-field test. Moreover, we also evaluated the depressive and anxiety-like behavior of P2X7-null mice in forced swimming test, open-field test, and elevated plus maze.ResultsAlong with stress accumulation, extracellular ATP, cleaved-caspase 1, IL-1β, and ASC were significantly enhanced in the hippocampus, but P2X7R and NLRP3 were not. Immunoprecipitation assay indicated that along with the accumulation of stress, assembly of NLRP3 inflammasome and cleaved caspase 1 in NLRP3 inflammasome were significantly increased. Moreover, antagonists of P2X7R, either BBG or A438079, prevented the development of depressive-like behaviors induced by chronic unpredictable stress in rats. Meanwhile, we could not observe any depressive-like or anxiety-like behaviors of P2X7-null mice after they had been exposed to CUS. The results implied that P2X7 knockout could impede the development of depressive-like and anxiety-like behaviors induced by CUS. In contrast, chronic administration of agonists of P2X7R, either ATP or BzATP, could induce depressive-like behaviors.ConclusionsThe activation of P2X7R and subsequent NLRP3 inflammasome in hippocampal microglial cells could mediate depressive-like behaviors, which suggests a new therapeutic target for the prevention and treatment of depression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0865-y) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors

Yue

Huang

Zhu

et al. 2017

J Neuroinflammation

255

174

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“…In fact, various SNPs in genes coding for both IL-1β and IL-1R2 have been linked to increases in both state and trait anxiety [23]. IL-1β gene polymorphisms also affect an individual’s response to stress events to predispose individuals to anxiety and depression disorders [24] underscoring the importance of IL-1β to anxiety and mood disorders in humans. Given that fasting is known to reduce some of the sickness symptoms associated with the peripheral administration of IL-1β [25], we sought to show, that in the healthy state, fasting has a beneficial impact on anxiety, and this is mechanistically tied to inhibition of IL-1β priming and activation within the brain.…”

Section: Introductionmentioning

confidence: 99%

Acute fasting inhibits central caspase-1 activity reducing anxiety-like behavior and increasing novel object and object location recognition

et al. 2017

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Background Inflammation within the central nervous system (CNS) is frequently comorbid with anxiety. Importantly, the pro-inflammatory cytokine most commonly associated with anxiety is IL-1β. The bioavailability and activity of IL-1β is regulated by caspase-1-dependent proteolysis vis-a-vis the inflammasome. Thus, interventions regulating the activation or activity of caspase-1 should reduce anxiety especially in states that foster IL-1β maturation. Methods Male C57BL/6j, C57BL/6j mice treated with the capase-1 inhibitor biotin-YVAD-cmk, caspase-1 knockout (KO) mice and IL-1R1 KO mice were fasted for 24 hours or allowed ad libitum access to food. Immediately after fasting, caspase-1 activity was measured in brain region homogenates while activated caspase-1 was localized in the brain by immunohistochemistry. Mouse anxiety-like behavior and cognition were tested using the elevated zero maze and novel object/object location tasks, respectively. Results A 24 h fast in mice reduced the activity of caspase-1 in whole brain and in the prefrontal cortex, amygdala, hippocampus, and hypothalamus by 35%, 25%, 40%, 40%, and 40% respectively. A 24 h fast also reduced anxiety-like behavior by 40% and increased novel object and object location recognition by 21% and 31%, respectively. IL-1β protein, however, was not reduced in the brain by fasting. ICV administration of YVAD decreased caspase-1 activity in the prefrontal cortex and amygdala by 55%, respectively leading to a 64% reduction in anxiety like behavior. Importantly, when caspase-1 KO or IL1-R1 KO mice are fasted, no fasting-dependent reduction in anxiety-like behavior was observed. Conclusions Results indicate that fasting decrease anxiety-like behavior and improves memory by a mechanism tied to reducing caspase-1 activity throughout the brain.

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“…Disturbances in the genetic expression pro le of proinᴀammatory cytokines such as Interleukin-1B (IL-1B) and Interleukin-6 (IL-6) has been reported to inᴀuence these mood disorder pheontypes profoundly, however it has been also shown that different stressors are needed to exert such effect. That means that signi cant main effects of these genes on depression and anxiety are lacking, but highly signi cant interaction effects could be observed even after correcting for multiple testing [1,2] The aim of this study was to represent how the different stress clusters can interact with two IL-1B, and an IL-6 polymorphisms, inᴀuencing anxiety phenotype in a normal population sample from Hungary. For the analysis 1093 people were recruited, provided genetic samples and phenotypic information.…”

Section: Mta-se Neuropsychopharmacology and Neurochemistry Research Gmentioning

confidence: 99%

“…For the analysis 1093 people were recruited, provided genetic samples and phenotypic information. Linear regression analyses were carried out with PLINK (1,2) ( This study provides an example for the interplay among interaction patterns in the pathomechanism of anxiety symptoms. Among the examined stress types we found that IL-1B polymorphisms are more sensitive to early life stress than any other interaction we found.…”

Section: Mta-se Neuropsychopharmacology and Neurochemistry Research Gmentioning

confidence: 99%

mentioning

confidence: 99%

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Interleukin-6 and interleukin-1B polymorphisms show different interaction patterns with stressors on trait anxiety

Kovács¹,

Eszlári²,

Petschner³

et al. 2016

European Neuropsychopharmacology

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Neuroinᴀammatory mechanisms received more and more attention recently in neuroscience examining depression and anxiety. Disturbances in the genetic expression pro le of proinᴀammatory cytokines such as Interleukin-1B (IL-1B) and Interleukin-6 (IL-6) has been reported to inᴀuence these mood disorder pheontypes profoundly, however it has been also shown that different stressors are needed to exert such effect. That means that signi cant main effects of these genes on depression and anxiety are lacking, but highly signi cant interaction effects could be observed even after correcting for multiple testing [1,2]

show abstract

Effects of IL1B single nucleotide polymorphisms on depressive and anxiety symptoms are determined by severity and type of life stress

Cited by 50 publications

References 51 publications

Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors

Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors

Acute fasting inhibits central caspase-1 activity reducing anxiety-like behavior and increasing novel object and object location recognition

Interleukin-6 and interleukin-1B polymorphisms show different interaction patterns with stressors on trait anxiety

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