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Cited by 124Tryptophan and brain disordersStress Responses and CortisolNeuroinflammation and Neurodegeneration Mechanisms

Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety

Open access
Niraula, Anzela, Witcher, Kristina G., Sheridan, John F., Godbout, Jonathan P.·2019·Biological Psychiatry
DOI 10.1016/j.biopsych.2018.09.030PMC PMC6440848
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Abstract

Background: Interleukin (IL)-6 is elevated in circulation with chronic stress and may contribute to neurobehavioral complications. We have reported that repeated social defeat (RSD) stress in mice caused recruitment of proinflammatory monocytes to the brain and triggered the onset of anxiety-like behavior. Therefore, the purpose of this study was to determine the role of IL-6 signaling in the peripheral immune response, neuroinflammation, and anxiety following stress. Methods: WT and IL-6KO mice were subjected to RSD, and immune and behavioral parameters were determined 14 hours later. Results: Although monocyte release and recruitment to the brain during stress were maintained in the IL-6KO mice, anxiety and social avoidance were prevented. NanoString analysis of FAC-sorted blood monocytes (CD11b+/Ly6Chi) and brain monocytes (CD11b+/CD45hi) revealed a unique pattern of immune-related gene expression that was dependent on stress and IL-6. For instance, blood monocytes after stress had a transcriptional signature and immune profile consistent with priming, which was attenuated in monocytes from IL-6KO stress mice. Moreover, the monocytes recruited to the brain and associated with the development of anxiety had a transcriptional signature (enhanced IL-1β, CD14, Mmp9, MyD88, Ager, Stat3) that was dependent on IL-6. Conclusions: Here, we show the effects of IL-6 on the transcriptional signature of monocytes in circulation and brain after stress. Overall, robust increases in IL-6 after stress induced a primed profile in monocytes that were recruited to the brain and propagated IL-1-mediated inflammation and anxiety.

AI snapshot

Written from the paper’s full text.

TL;DR

Repeated social defeat (RSD) in mice elevated plasma IL-6, and IL-6 deficiency prevented stress-induced anxiety and social avoidance even though monocyte release and brain recruitment still occurred. IL-6 was required for a primed blood monocyte transcriptional signature and for the inflammatory/IL-1β signature of monocytes recruited to the brain.

Key findings

  • IL-6KO mice were protected from RSD-induced anxiety and social avoidance: WT-Stress mice had fewer center entries and less center time in the open field and less interaction-zone time and more corner-zone time in the social trial than all other groups (p<0.05 for post hoc comparisons).
  • Stress increased plasma IL-6 (p<0.05), which was prevented in IL-6KO mice (stress × genotype, p<.01), but stress still increased bone marrow and circulating monocytes/granulocytes (p<.0001) and brain CD11b+/CD45hi monocyte accumulation (p<.001) independent of genotype.
  • NanoString analysis of 279 immune genes showed 37 stress-altered genes in blood monocytes, with 7 reversed in IL-6KO-Stress mice; in brain monocytes, 46 genes were stress-altered, with 12 IL-6-dependent, including Il-1β, Ly6C, Mmp9, and Cd14.
  • Brain monocyte stress increases in Ager, Alox5, Cd14, Ccr1, Cxcl2, IL-1β, Mmp9, Myd88, and Stat3 were prevented by IL-6 deficiency; ex vivo LPS-stimulated PBMCs from WT-Stress mice had the highest IL-6 and IL-1β levels compared with all other groups (p<.05).

Methods

  • Male WT and IL-6KO C57BL/6 mice underwent RSD: an aggressive CD-1 mouse was introduced for 2 h daily for six consecutive days; behavior and tissues were assessed 14 h after the last stress cycle.
  • Blood monocytes (CD11b+/Ly6Chi) and brain monocytes (CD11b+/CD45hi) were FAC-sorted for NanoString nCounter Mouse Inflammation v2 Panel Plus analysis of 279 genes, with nSolver normalization and IPA upstream-regulator comparison.
  • Peripheral blood mononuclear cells were isolated and stimulated ex vivo with LPS for 18 h; data were analyzed by two-way (stress × intervention) ANOVA with F-protected t tests.

Limitations

  • The paper states that it does not prove IL-6 is the direct cause of anxiety-like behavior after stress, and that the mechanism underlying IL-6-induced monocyte priming remains unknown.
  • The paper notes that corticosterone levels were not tested in IL-6KO mice after stress, although it argues the corticosterone response was likely unaltered based on unchanged circulating monocytes and ICAM-1.
  • Evident from the text: the study used male mice only, and the central evidence for monocyte-specific IL-6/Stat3 signaling is transcriptional and correlational rather than a direct monocyte-specific manipulation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.biopsych.2018.09.030

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 52 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The stress-induced increase in plasma IL-6 is prevented in IL-6KO mice.

    “this increase was prevented in the IL-6KO mice (Fig. 2A, stress x genotype, p<.01)”
    Quote in the paperSubstantial claim
  • Findingown data

    Stress increases plasma IL-6 in wildtype mice.

    “As expected, stress increased plasma IL-6 (Fig. 2A, p<0.05)”
    Quote in the paperSubstantial claim
  • Findingown data

    Stress increases Iba-1 proportional area in the prelimbic cortex, CA3, and dentate gyrus.

    “Stress increased Iba-1 proportional area in the PrL (Fig. 3A&B, p<.001), CA3 (Fig. 3C, p<.01), and dentate gyrus (Fig. 3D, p<.01).”
    Quote in the paperSubstantial claim
  • Findingown data

    The stress-induced increases in bone marrow and circulating myeloid cells are independent of genotype (IL-6).

    “These immune responses to stress were independent of genotype.”
    Quote in the paperSubstantial claim
  • Findingown data

    Stress increases RNA copy number of inflammatory genes (Ly6c, Mmp9, Cxcr2, Alox5, Ccr1) and glucocorticoid sequestration gene Fkbp5 in blood monocytes.

    “Pairwise comparisons indicated that stress increased (p<.05) the RNA copy number of several key inflammatory (Ly6c, Mmp9, Cxcr2, Alox5, Ccr1) and glucocorticoid sequestration (Fkbp5) genes in blood monocytes.”
    Quote in the paperSubstantial claim
  • May combine two claims. 31
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingown data

    Stress increases IL-1β mRNA expression in enriched CD11b+ cells, and this increase is prevented in IL-6KO mice.

    “Collectively, stress caused microglia activation and monocyte recruitment to the brain independent of genotype, but the corresponding induction of IL-1β was prevented in IL-6KO mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Blood monocytes after stress have a transcriptional signature and immune profile consistent with priming, which is attenuated in monocytes from IL-6KO stress mice.

    “For instance, blood monocytes after stress had a transcriptional signature and immune profile consistent with priming, which was attenuated in monocytes from IL-6KO stress mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Stress increases expression of inflammatory-related molecules Ager, Alox5, Cd14, Ccr1, Cxcl2, IL-1β, Mmp9, Myd88, and Stat3 in brain monocytes, and all these increases are prevented by IL-6 deficiency.

    “Overall, stress increased (p<0.05) expression of several inflammatory-related molecules: Ager, Alox5, Cd14, Ccr1, Cxcl2, IL-1β, Mmp9, Myd88 and Stat3. All of these stress-associated increases were prevented by IL-6 deficiency.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Stress increases the percentage of monocytes (CD11b+/Ly6Chi) and granulocytes (CD11b+/Ly6G+) in the bone marrow.

    “Stress also increased the percentage of monocytes (CD11b+/Ly6Chi) and granulocytes (CD11b+/Ly6G+) in the bone marrow (Fig. 2B-D, p<.0001)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Stress-induced anxiety and social avoidance are prevented in IL-6 deficient mice.

    “Collectively, stress-induced anxiety and social avoidance were prevented in the IL-6KO mice.”
    • Also stated in: § Results: · plain
      “Although monocyte release and recruitment to the brain during stress were maintained in the IL-6KO mice, anxiety and social avoidance were prevented.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Stress alters the expression of 46 immune genes in brain monocytes, of which 12 are dependent on IL-6, including Il-1β, Ly6C, Mmp9, and Cd14.

    “Taken together, stress altered the expression of 46 immune genes in brain monocytes, of which 12 were dependent on IL-6, including key inflammatory molecules (Il-1β, Ly6C, Mmp9 and Cd14).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Stress increases the percentage of monocytes (CD11b+/Ly6Chi) and granulocytes (CD11b+/Ly6G+) in circulation.

    “and circulation (Fig. 2E-G, p<.0001)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Stress alters the expression of 37 immune genes in blood monocytes, of which 7 are reversed in IL-6KO mice.

    “Taken together, stress altered the expression of 37 immune genes in monocytes, of which 7 were reversed in IL-6KO group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Stress-induced anxiety-like behavior and social avoidance were prevented in IL-6KO mice.

    “A key finding of this study was that stress-induced anxiety-like behavior and social avoidance were prevented in IL-6KO mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Stat3, a key transcription factor in IL-6 signaling, was increased in the brain monocytes of the WT-Stress mice but not in the IL-6KO-Stress mice.

    “Notably, Stat3, a key transcription factor in IL-6 signaling was increased in the brain monocytes of the WT-Stress mice but not in the IL-6KO-Stress mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Stat3 expression was increased in the brain monocytes after stress, but this change was not evident in the blood monocytes.

    “Although Stat3 expression was increased in the brain monocytes after stress, this change was not evident in the blood monocytes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    IL-6 deficiency was not associated with reduction in circulating monocytes (Fig. 2F) or ICAM-1 (data not shown).

    “Since, in the current study, IL-6 deficiency was not associated with reduction in circulating monocytes (Fig. 2F) or ICAM-1 (data not shown), the corticosterone response to stress was likely unaltered in the IL-6KO mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL-6 deficiency did not prevent microglial activation or monocyte recruitment to the brain during stress.

    “Notably, IL-6 deficiency did not prevent microglial activation or monocyte recruitment to the brain during stress; however, it blocked anxiety-like behavior.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Peripheral blood cells isolated from stressed individuals show increased production of spontaneous IL-6 and in response to immune challenge.

    “Peripheral blood cells isolated from stressed individuals show increased production of spontaneous IL-6 and in response to immune challenge [12, 13].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Miller, 2014, Greater inflammatory activity and blunted glucocorticoid signaling in monocytes of chronically stressed caregivers, Brain Behav Immun source

      Not checked in the free run.

    • cites [13] Gola, 2013, Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells, BMC Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    IL-6 production during RSD primes peripheral monocytes that traffic to the brain and augment IL-1β signaling that is associated with anxiety-like behavior.

    “Here, we show novel data that IL-6 production during RSD primes peripheral monocytes that traffic to the brain and augment IL-1β signaling that is associated with anxiety-like behavior.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The differences observed in IL-6KO mice are due to the absence of IL-6 signaling during stress rather than developmental or compensatory effects of the IL-6 knockout.

  • May combine two claims.

    Premisecitation

    IL-6 is a consistently elevated biomarker of chronic stress in long-term caregivers, early life adversity, and depressed individuals that attempted suicide.

    “IL-6 is a consistently elevated biomarker of chronic stress in long-term caregivers [8], early life adversity [9], and depressed individuals that attempted suicide [10].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] Steptoe, 2007, The effects of acute psychological stress on circulating inflammatory factors in humans: A review and meta-analysis, Brain Behav Immun source

      Not checked in the free run.

    • cites [9] Carpenter, 2010, Association between plasma IL-6 response to acute stress and early-life adversity in healthy adults, Neuropsychopharmacology source

      Not checked in the free run.

    • cites [10] Lindqvist, 2009, Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity, Biol Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    High levels of CRP and IL-6 are reported in individuals with anxiety disorders.

    “High levels of CRP and IL-6 were also reported in individuals with anxiety disorders [6, 7].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Vogelzangs, 2013, Anxiety disorders and inflammation in a large adult cohort, Transl Psychiatry source

      Not checked in the free run.

    • cites [7] O’Donovan, 2010, Clinical anxiety, cortisol and interleukin-6: Evidence for specificity in emotion-biology relationships, Brain Behav Immun source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Robust increases in IL-6 after stress induce a primed profile in monocytes that are recruited to the brain and propagate IL-1-mediated inflammation and anxiety.

    “Overall, robust increases in IL-6 after stress induced a primed profile in monocytes that were recruited to the brain and propagated IL-1-mediated inflammation and anxiety.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The differences observed in IL-6KO mice are due to the absence of IL-6 signaling during stress rather than developmental or compensatory effects of the IL-6 knockout.

  • May combine two claims.

    Premisecitation

    Interventions with noradrenergic receptor antagonists or GABAergic agonists prevent RSD-induced IL-6 increase, monocyte recruitment to the brain, and anxiety-like behavior.

    “Interventions with noradrenergic receptor antagonist or GABAergic agonists prevented RSD-induced IL-6 increase, monocyte recruitment to the brain, and anxiety-like behavior following RSD [24, 25].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Ramirez, 2016, GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations, Brain Behav Immun source

      Not checked in the free run.

    • cites [25] Wohleb, 2011, β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic stress and overexpression of central IL-6 trigger depressive-like behavior in rats, an effect unaltered by SSRI but prevented by IL-6 antibodies.

    “For example, chronic stress and overexpression of central IL-6 triggered depressive-like behavior in rats – an effect unaltered by SSRI, but prevented by treatment with IL-6 antibodies [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Sukoff Rizzo, 2012, Evidence for sustained elevation of IL-6 in the CNS as a key contributor of depressive-like phenotypes, Transl Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Repeated social defeat in mice promotes accumulation of peripheral monocytes in the brain that augment IL-1β signaling and cause prolonged anxiety-like behavior.

    “We have reported that repeated social defeat (RSD) in mice promoted the accumulation of peripheral monocytes in the brain that augmented IL-1β signaling and caused prolonged anxiety-like behavior [21, 22].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] McKim, 2018, Microglial recruitment of IL-1β-producing monocytes to brain endothelium causes stress-induced anxiety, Mol Psychiatry source

      Not checked in the free run.

    • cites [22] Wohleb, 2013, Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior, J Neurosci source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-6 is a consistent cytokine biomarker in clinical and experimental reports of chronic stress.

    “Interleukin-6 (IL-6) is a consistent cytokine biomarker in clinical and experimental reports of chronic stress and is associated with treatment-resistant mood disorders, increased morbidity and mortality [16, 28].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Hodes, 2014, Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [28] Kiecolt-Glaser, 2003, Chronic stress and age-related increases in the proinflammatory cytokine IL-6, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Peripheral IL-6 may directly enter the brain via increased blood-brain barrier permeability and promote social avoidance following social defeat stress.

    “A recent study indicated that peripheral IL-6 may directly enter the brain via increased blood-brain barrier permeability and promote social avoidance following social defeat stress [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Menard, 2017, Social stress induces neurovascular pathology promoting depression, Nat Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice with social avoidance following social defeat stress have higher IL-6 levels compared to resilient mice, and this effect is prevented with IL-6 antibody treatment.

    “Furthermore, mice with social avoidance (“susceptible”) following exposure to social defeat stress had higher IL-6 levels compared to those that did not develop social avoidance (“resilient”), and this effect was prevented with IL-6 antibody treatment [16].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Hodes, 2014, Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of antibodies targeting IL-6 prevented stress-induced IL-6 production and social avoidance behavior.

    “Administration of antibodies targeting IL-6 prevented stress-induced IL-6 production and social avoidance behavior [16].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Hodes, 2014, Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A single episode of stress is sufficient to induce social avoidance.

    “For example, a single episode of stress does not trigger an immune response that is critical for anxiety, but it is sufficient to induce social avoidance [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Wohleb, 2014, Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain, Biol Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    IL-6 is associated with treatment-resistant mood disorders, increased morbidity and mortality.

    “Interleukin-6 (IL-6) is a consistent cytokine biomarker in clinical and experimental reports of chronic stress and is associated with treatment-resistant mood disorders, increased morbidity and mortality [16, 28].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Hodes, 2014, Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [28] Kiecolt-Glaser, 2003, Chronic stress and age-related increases in the proinflammatory cytokine IL-6, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A single episode of stress does not trigger an immune response that is critical for anxiety.

    “For example, a single episode of stress does not trigger an immune response that is critical for anxiety, but it is sufficient to induce social avoidance [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Wohleb, 2014, Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transcriptional analysis of blood monocytes from stressed humans revealed an increased expression of chemotaxis and inflammation-related genes, and a corresponding decrease in regulatory (CX3CR1) genes, viral response genes, and glucocorticoid signaling genes.

    “Transcriptional analysis of blood monocytes from stressed humans revealed an increased expression of chemotaxis and inflammation-related genes, and a corresponding decrease in regulatory (CX3CR1) genes, viral response genes, and glucocorticoid signaling genes [12, 32].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Miller, 2014, Greater inflammatory activity and blunted glucocorticoid signaling in monocytes of chronically stressed caregivers, Brain Behav Immun source

      Not checked in the free run.

    • cites [32] Miller, 2008, A functional genomic fingerprint of chronic stress in humans: Blunted glucocorticoid and increased NF-kappaB signaling, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    It is likely that IL-6 operates on multiple levels and regulates social avoidance differentially on a neuronal circuitry level.

    “Because IL-6KO-Stress mice were resistant to social avoidance in our current study, it is likely that IL-6 operates on multiple levels and regulates social avoidance differentially on a neuronal circuitry level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Peripheral IL-6 can enter the brain and influence the social avoidance response.

    “Recent studies modeling social stress in mice indicate that peripheral IL-6 can enter the brain and influence the social avoidance response [20].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Menard, 2017, Social stress induces neurovascular pathology promoting depression, Nat Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In PTSD studies, stress-induced increases in inflammatory genes and decreases in antigen-presentation molecules (HLA-DQB1 in humans) and apoptosis-related genes (Birc2) were detected.

    “In PTSD studies, stress-induced increases in inflammatory genes and decreases in antigen-presentation molecules (HLA-DQB1 in humans) and apoptosis-related genes (Birc2) were detected [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Segman, 2005, Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors, Mol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice susceptible or resilient to social avoidance after stress had higher and lower levels of plasma IL-6, respectively.

    “In addition, mice susceptible or resilient to social avoidance after stress had higher and lower levels of plasma IL-6, respectively [16].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Hodes, 2014, Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The attenuated inflammatory profile in brain monocytes in absence of IL-6 was associated with overall reduced inflammatory signaling in the brain and an absence of anxiety-like behavior.

    “In absence of IL-6, monocytes in the brain showed an attenuated inflammatory profile, including reduced IL-1β expression, which was associated with overall reduced inflammatory signaling in the brain and an absence of anxiety-like behavior.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The key event is the induction of the pro-inflammatory phenotype in the recruited monocytes, which depends on IL-6.

    “The key event is the induction of the pro-inflammatory phenotype in the recruited monocytes, which we demonstrate depends on IL-6.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microglia activated during stress produce chemokines to recruit IL-1β-expressing monocytes that propagate IL-1 signaling into the brain via the vascular endothelium.

    “Microglia activated during stress produce chemokines to recruit IL-1β-expressing monocytes that propagate IL-1 signaling into the brain via the vascular endothelium [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] McKim, 2018, Microglial recruitment of IL-1β-producing monocytes to brain endothelium causes stress-induced anxiety, Mol Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    The more homogenous subpopulation (reactive/inflammatory) of monocytes that accumulate in the brain versus the more diverse monocyte population in the blood may explain the difference in Stat3.

    “This may be related to the more homogenous subpopulation (reactive/inflammatory) of monocytes that accumulate in the brain versus the more diverse monocyte population in the blood.”
    Quote in the paperNot a substantial claim
37 of 37

  • The paper relies on this without support.

    The differences observed in IL-6KO mice are due to the absence of IL-6 signaling during stress rather than developmental or compensatory effects of the IL-6 knockout.

    “Breeding triads of IL-6KO mice on the C57BL/6 background were purchased from Jackson Laboratories (Bar Harbor, ME).”
    “As expected, stress increased plasma IL-6 (Fig. 2A, p<0.05) and this increase was prevented in the IL-6KO mice (Fig. 2A, stress x genotype, p<.01).”

  • The paper relies on this without support.

    There is little information on the functional effects of high IL-6 on the physiological, behavioral, and immunological response to stress.

    “Nonetheless, there is little information on the functional effects of high IL-6 on the physiological, behavioral, and immunological response to stress.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Stress-induced monocyte recruitment to the brain resulted in anxiety and social avoidance in wild-type mice, and in IL-6 knockout mice, avoidance behaviors were prevented despite maintained immune cell recruitment.

    “Furthermore, stress-induced monocyte recruitment to the brain resulted in anxiety and social avoidance in wild-type mice. In IL-6 knockout mice, avoidance behaviors were prevented despite maintained immune cell recruitment [59].”

    From Baseline Pro-Inflammatory Cytokine Levels Moderate Psychological Inflexibility in Behavioral Treatment for Chronic Pain (2022) · cites this paper as [59]

    The Results report anxiety-like behavior and social avoidance in stressed wild-type mice, while both were prevented in IL-6 knockout mice despite maintained monocyte recruitment to the brain. The Discussion cautions that the presence of recruited monocytes alone does not cause anxiety; it identifies their IL-6-dependent inflammatory phenotype as key and discusses social avoidance as potentially involving a different mechanism. Thus, the claim overstates recruitment itself as the cause of both behaviors. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In chronic models of stress, blocking antibodies to IL6Ra, which do not cross the blood brain barrier, promoted resilience to social stress.

    “Our findings that hepatocyte expression of Il6ra is required for normal behavioral response to acute stress are in line with recent studies using chronic models of stress (Hodes et al., 2014; Niraula et al., 2019; Zhang et al., 2017), where the use of blocking antibodies to IL6Ra, which do not cross the blood brain barrier (Nellan et al., 2018), promoted resilience to social stress.”

    From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Niraula et al., 2019

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Authors
Niraula, A., Witcher, K. G., Sheridan, J. F., & Godbout, J. P.
Affiliations
The Ohio State University (US)
Corresponding author
  • Sheridan, John F.
  • Godbout, Jonathan P.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2019-04
Volume
85
Issue
8
Pages
679-689
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2018.09.030
PMC
PMC6440848
OpenAlex
W2896061350
Semantic Scholar
a87f3f0adf9917243616382b47a287e588b2d1c7
Cited by
124
References
38
Citations by year
2026: 13 · 2025: 9 · 2024: 20 · 2023: 20 · 2022: 22 · 2021: 18 · 2020: 10 · 2019: 12
FWCI
3.17
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (R01-MH-093473, R01-MH097243)
  • National Institute of Aging (R01-AG033028)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
interleukin-6, social defeat stress, anxiety, monocytes, neuroinflammation, monocyte priming, IL-1β, CD14, MyD88, STAT3, MMP-9, AGER, social avoidance, chronic stress, IL-6 knockout mice, gene expression signatures
MeSH terms
Animals, Anxiety, Behavior, Animal, Brain, Male, Monocytes, Stress, Psychological, Interleukin-6, Gene Expression, Mice, Knockout, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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