Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal

May combine two claims.

Stress can stimulate myeloid differentiation by increasing GM-CSF, and GM-CSF signaling mediates differentiation of granulocytes and monocytes from their common progenitor GM-CFU.

“In opposition to CXCL12, stress can stimulate myeloid differentiation by increasing the myelopoietic growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF).”

• Also stated in: § RSD-RESPONSIVE NEUROENDOCRINE PATHWAYS ALTER HOMEOSTATIC HEMATOPOIESIS: ENHANCED MYELOPOIESIS LEADS TO PRODUCTION OF PRIMED AND GC-RESISTANT MYELOID CELLS · plain

  “Specifically, GM-CSF signaling mediates differentiation of granulocytes and monocytes from their common progenitor, granulocytemacrophage colony-forming unit (GM-CFU) (Hamilton and Achuthan, 2013).”

• cites Hamilton and Achuthan, 2013 sourceNot checked yet

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May combine two claims.

Prolonged or severe stress exposure disrupts homeostatic communication between the CNS and peripheral immune system, shifting immune signaling toward a proinflammatory state.

“Prolonged or severe stress exposure disrupts homeostatic or 'healthy' communication between the CNS and peripheral immune system, shifting immune signaling toward a proinflammatory state.”

May combine two claims.

RSD significantly decreases B-cell and T-cell lymphocytes in the BM and circulation, thereby shifting hematopoiesis to produce myeloid lineage cells.

“In fact, RSD significantly decreases B-cell and T-cell lymphocytes in the BM and circulation (Engler et al, 2004;McKim et al, 2015), thereby shifting hematopoiesis to produce myeloid lineage cells.”

• cites Engler et al, 2004 sourceNot checked yet

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• cites McKim et al, 2015 sourceNot checked yet

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Classified as probably not a substantial claim.

Dysregulated or enhanced neuroinflammation facilitates the etiology of mood disorders, particularly in treatment-resistant depressed patients.

“Dysregulated or enhanced neuroinflammation is argued to facilitate the etiology of mood disorders, particularly in treatment-resistant depressed patients (Hodes et al, 2015).”

• cites Hodes et al, 2015 sourceNot checked yet

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May combine two claims.

NE decreases the inhibitory chemokine CXCL12, and stress-induced hematopoietic stem cell differentiation is associated with decreased CXCL12 expression in the BM.

“One such way that leukocytes are stimulated by NE is by decreasing the inhibitory chemokine CXCL12 (Katayama et al, 2006;Heidt et al, 2014).”

• Also stated in: § RSD-RESPONSIVE NEUROENDOCRINE PATHWAYS ALTER HOMEOSTATIC HEMATOPOIESIS: ENHANCED MYELOPOIESIS LEADS TO PRODUCTION OF PRIMED AND GC-RESISTANT MYELOID CELLS · plain

  “As such, stress-induced hematopoietic stem cell differentiation was associated with decreased CXCL12 expression in the BM.”

• cites Katayama et al, 2006 sourceNot checked yet

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• cites Heidt et al, 2014 sourceNot checked yet

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May combine two claims.

RSD is accompanied by activation of stress-reactive neurocircuitry, prolonged anxiety-like behavior, and neuroinflammatory events including microglial activation and increased cytokine production.

“As illustrated in Figure 1, RSD is accompanied by activation of stress-reactive neurocircuitry, prolonged anxiety-like behavior, and neuroinflammatory events including microglial activation and increased cytokine production.”

Classified as probably not a substantial claim.

Activation of proinflammatory signaling molecules engages neural mechanisms that mediate changes to mood, cognition, and physiology that are adaptive for host defense against infection or injury (sickness response).

“This argument comes from the observation that activation of proinflammatory signaling molecules engage neural mechanisms that mediate changes to mood, cognition, and physiology that are adaptive for the host defense against infection or injury (ie, the 'sickness' response) (Dantzer et al, 1998;Maier and Watkins, 1998).”

• cites Dantzer et al, 1998 sourceNot checked yet

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• cites Maier and Watkins, 1998 sourceNot checked yet

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May combine two claims.

The myelopoietic response to RSD requires repeated bouts with the aggressor, as monocytes begin to accumulate in circulation after three cycles of social defeat and are robustly increased after six cycles.

“The myelopoietic response to RSD requires repeated bouts with the aggressor, as monocytes begin to accumulate in circulation after three cycles of social defeat and are robustly increased after six cycles (Wohleb et al, 2013).”

• cites Wohleb et al, 2013 sourceNot checked yet

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May combine two claims.

Repeated or chronic stressors activate sympathetic signaling that reduces CXCL12 and increases GM-CSF, thereby enhancing immune cell production toward the myeloid cell lineage.

“As such, repeated or chronic stressors activate sympathetic signaling that reduces CXCL12 and increases GM-CSF, thereby enhancing immune cell production toward the myeloid cell lineage.”

May combine two claims.

RSD preferentially increases the amount of circulating Ly6C hi monocytes, which is prevented by blockage of the β-adrenergic receptor.

“Based on data from flow cytometry scatter properties, RSD preferentially increases the amount of circulating Ly6C hi monocytes (Powell et al, 2013;Wohleb et al, 2013;Ramirez et al, 2015a) that is prevented by blockage of the β-adrenergic receptor (Hanke et al, 2012;Powell et al, 2013).”

• cites Powell et al, 2013 sourceNot checked yet

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• cites Wohleb et al, 2013 sourceNot checked yet

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• cites Ramirez et al, 2015aNot checked yet

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May combine two claims.

These data indicate that RSD promotes accumulation of innately GC-insensitive monocytes, underlying the stress-induced proinflammatory phenotype.

“These data indicate that RSD promotes accumulation of innately GC-insensitive monocytes, underlying the stress-induced proinflammatory phenotype.”

May combine two claims.

RSD also increases depressive-like behaviors, including social avoidance, and these effects can persist at least 8 days after stressor termination with some persisting up to 24 days.

“RSD also increases depressive-like behaviors, including social avoidance (Wohleb et al, 2012;Ramirez et al, 2015b).”

• Also stated in: § RSD ACTIVATES STRESS CIRCUITRY, PROMOTES NEUROINFLAMMATION, AND AFFECTS BEHAVIOR · plain

  “It is important to note that the effects of RSD can be long lasting, as many of these behavioral changes persist at least 8 days after stressor termination with some (social avoidance) persisting up to 24 days later (Ramirez et al, 2015b).”

• cites Wohleb et al, 2012 sourceNot checked yet

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• cites Ramirez et al, 2015bNot checked yet

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May combine two claims.

Newly differentiated monocytes produced by chronic stress have increased trafficking capabilities and a primed proinflammatory phenotype compared with typical monocytes during healthy or homeostatic conditions.

“As such, newly differentiated monocytes produced by chronic stress have increased trafficking capabilities and a primed proinflammatory phenotype compared with that of the typical monocyte during 'healthy' or homeostatic conditions (Figure 2).”

Classified as probably not a substantial claim.

These cells are termed 'primed' because they produce enhanced proinflammatory signaling molecules and bactericidal activity when stimulated with an immune challenge.

“These cells are termed 'primed' because they produce enhanced proinflammatory signaling molecules and bactericidal activity when stimulated with an immune challenge (Bailey et al, 2007;Powell et al, 2009).”

• cites Bailey et al, 2007 sourceNot checked yet

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• cites Powell et al, 2009 sourceNot checked yet

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May combine two claims.

Under RSD, exposure increased the presence of GFP+ cells specifically in brain regions associated with fear, anxiety, and threat appraisal, including the hypothalamus, amygdala, and hippocampus, while BBB permeability was unaffected.

“Although BBB permeability was unaffected as indicated by the Evan's blue dye test, exposure to RSD increased the presence GFP+ cells specifically in brain regions associated with fear, anxiety, and threat appraisal, including the hypothalamus, amygdala, and hippocampus (Wohleb et al, 2013).”

• cites Wohleb et al, 2013 sourceNot checked yet

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May combine two claims.

Microglia are activated in a variety of stress models and are argued to contribute to the maladaptive effects of stress.

“Therefore, microglia are activated in a variety of stress models, and is argued to contribute to the maladaptive effects of stress.”

May combine two claims.

Chronic unpredictable stress increases GCs during the diurnal zenith but not nadir, and increases monocytes and neutrophils in the spleen, similar to RSD.

“For example, a recent study reported that 8 weeks of chronic unpredictable stress increased GCs during the diurnal zenith but GC levels during the diurnal nadir were normal (Monteiro et al, 2015).”

• Also stated in: § RSD-RESPONSIVE NEUROENDOCRINE PATHWAYS ALTER HOMEOSTATIC HEMATOPOIESIS: ENHANCED MYELOPOIESIS LEADS TO PRODUCTION OF PRIMED AND GC-RESISTANT MYELOID CELLS · plain

  “This was accompanied by increased population of monocytes and neutrophils, but not eosinophils, in the spleen.”

• cites Monteiro et al, 2015 sourceNot checked yet

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May combine two claims.

Chronic restraint stress is associated with diminished NK cell function, cytokine secretion, and enhanced viral replication, and its opposing immune effects on myeloid cells compared with RSD can be accounted for by differences in circulating GCs.

“For example, several studies investigated the immune response to chronic restraint stress and reported diminished natural killer (NK) cell function, cytokine secretion, and enhanced viral replication (Hunzeker et al, 2004;Tseng et al, 2005;Jin et al, 2013).”

• Also stated in: § RSD-RESPONSIVE NEUROENDOCRINE PATHWAYS ALTER HOMEOSTATIC HEMATOPOIESIS: ENHANCED MYELOPOIESIS LEADS TO PRODUCTION OF PRIMED AND GC-RESISTANT MYELOID CELLS · plain

  “The opposing immune effects on myeloid cells between RSD and chronic restraint can be accounted for by differences in circulating GCs.”

• cites Hunzeker et al, 2004 sourceNot checked yet

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• cites Tseng et al, 2005 sourceNot checked yet

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• cites Jin et al, 2013 sourceNot checked yet

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May combine two claims.

Daily treatment of clonazepam during RSD prevents myelopoiesis, although the same amount of biting from the aggressor persists, indicating that biting wounds are not sufficient to induce myelopoiesis of primed and GC-resistant monocytes.

“Daily treatment of clonazepam during RSD prevents myelopoiesis, although the same amount of biting from the aggressor persists, indicating that biting wounds are not sufficient to induce myelopoiesis of primed and GC-resistant monocytes (Ramirez et al, 2015a).”

• cites Ramirez et al, 2015aNot checked yet

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

Microglia are the predominant innate immune cell in the brain parenchyma and a key cell population that propagates neuroinflammatory signaling in the CNS.

“Microglia are the predominate innate immune cell in the brain parenchyma, and are a key cell population that propagates neuroinflammatory signaling in the CNS.”

May combine two claims.

The behavioral effects of RSD are indicative of enhanced fear/anxiety circuitry that is linked with anxiety and depression.

“The behavioral effects of RSD are indicative of enhanced fear/anxiety circuitry that is linked with anxiety and depression (Calhoon and Tye, 2015).”

• cites Calhoon and Tye, 2015 sourceNot checked yet

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

BM-derived monocytes traffic to and influence inflammatory signaling in the brain in models of severe trauma or advanced disease states.

“However, it has now been well demonstrated in models of severe trauma or advanced disease states that BM-derived monocytes traffic to and influence inflammatory signaling in the brain (Zhou et al, 2009;Grozdanov et al, 2014).”

• cites Zhou et al, 2009 sourceNot checked yet

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• cites Grozdanov et al, 2014 sourceNot checked yet

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May combine two claims.

RSD produces a robust increase in circulating GCs, but GC levels return to baseline within a few hours after the stress cycle and circadian rhythmicity is not affected.

“This produces a robust increase in circulating GCs but, importantly, GC levels return to baseline within a few hours after the stress cycle and circadian rhythmicity is not affected.”

• cites Hanke et al, 2012 sourceNot checked yet

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May combine two claims.

GC resistance is likely mediated by loss of anti-inflammatory feedback from the GC receptor, involving impaired GC receptor translocation and decreased FKBP52.

“GC resistance is likely mediated by loss of anti-inflammatory feedback from the GC receptor.”

• Also stated in: § RSD-RESPONSIVE NEUROENDOCRINE PATHWAYS ALTER HOMEOSTATIC HEMATOPOIESIS: ENHANCED MYELOPOIESIS LEADS TO PRODUCTION OF PRIMED AND GC-RESISTANT MYELOID CELLS · plain

  “Indeed, impaired nuclear trafficking of GC receptors in splenocytes was associated with decreased FKBP52, thereby increasing the ratio of FKBP51/FKBP2 in order to reduce GC receptor nuclear translocation (Jung et al, 2015).”

• cites Jung et al, 2015 sourceNot checked yet

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May combine two claims.

Inhibiting microglia during stress exposure with minocycline attenuated the increase of proinflammatory cytokines normally produced by stress and protected against stress-associated deficits in cognitive memory tasks and depressive-like and anxiety-like behaviors.

“In each case, inhibiting microglia during stress exposure attenuated the increase of proinflammatory cytokines normally produced by stress (Hinwood et al, 2012(Hinwood et al, , 2013;;Kreisel et al, 2014;McKim et al, 2016).”

• Also stated in: § RSD ACTIVATES STRESS CIRCUITRY, PROMOTES NEUROINFLAMMATION, AND AFFECTS BEHAVIOR · plain

  “Furthermore, minocycline protected against the development of stressassociated deficits in cognitive memory tasks in Morris water maze and Barnes maze (McKim et al, 2016) and depressivelike and anxiety-like behaviors such as reduced social interaction, sucrose preference, and open field exploration (Hinwood et al, 2012;Kreisel et al, 2014;Liu et al, 2015).”

• cites Hinwood et al, 2012 sourceNot checked yet

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• cites Kreisel et al, 2014 sourceNot checked yet

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• cites McKim et al, 2016 sourceNot checked yet

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May combine two claims.

RSD increases anxiety-like behaviors on standard measures including reduced exploration on open field and elevated plus maze, and increases dark preference in the light/dark test.

“For example, RSD increases anxiety-like behaviors on standard measures including reduced exploration on open field and elevated plus maze, and increases dark preference in the light/dark test (Wohleb et al, 2011(Wohleb et al, , 2013(Wohleb et al, , 2014b;;Hanke et al, 2012).”

• cites Wohleb et al, 2011 sourceNot checked yet

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• cites Wohleb et al, 2013 sourceNot checked yet

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• cites Hanke et al, 2012 sourceNot checked yet

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May combine two claims.

Newly generated monocytes produced by RSD are less mature and more inflammatory than homeostatic monocytes, expressing high levels of Ly6C and CCR2.

“An interesting characteristic of RSD is that the newly generated monocytes are less mature and more inflammatory than 'homeostatic' monocytes.”

• Also stated in: § RSD-RESPONSIVE NEUROENDOCRINE PATHWAYS ALTER HOMEOSTATIC HEMATOPOIESIS: ENHANCED MYELOPOIESIS LEADS TO PRODUCTION OF PRIMED AND GC-RESISTANT MYELOID CELLS · plain

  “Newly differentiated monocytes express high levels of the monocyte marker Ly6C (Ly6C hi ) (Rose et al, 2012).”

• cites Rose et al, 2012 sourceNot checked yet

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May combine two claims.

Newly differentiated Ly6c hi monocytes express surface activation markers that enhance immune function, including TLRs, CCR2, and co-stimulator receptors, which are upregulated by RSD.

“For example, surface activation markers including Toll-like receptors (TLRs), chemotactic receptors including CCR2, and co-stimulator receptors are upregulated by RSD (Avitsur et al, 2003;Engler et al, 2004;Bailey et al, 2007;Powell et al, 2009;Hanke et al, 2012).”

• cites Avitsur et al, 2003 sourceNot checked yet

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• cites Engler et al, 2004 sourceNot checked yet

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• cites Bailey et al, 2007 sourceNot checked yet

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May combine two claims.

RSD is associated with an increased neuroinflammatory profile characterized by increased cytokines (IL-1β, IL-6, TNF-α) and chemotactic CCL2, and reduced anti-inflammatory regulation of neuronal-derived fractalkine ligand (CX3CL1) and receptor (CX3CR1) expressed on microglia.

“RSD is associated with an increased neuroinflammatory profile characterized by increased cytokines (IL-1β, IL-6, TNF-α) and the chemotactic CCL2, and reduced anti-inflammatory regulation of neuronal-derived fractalkine ligand (CX 3 CL1) and receptor (CX 3 CR1) that are expressed on microglia (Wohleb et al, 2013(Wohleb et al, , 2014b;;Ramirez et al, 2015a).”

• cites Wohleb et al, 2013 sourceNot checked yet

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• cites Wohleb et al, 2014bNot checked yet

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• cites Ramirez et al, 2015aNot checked yet

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May combine two claims.

The repeated and chronic nature of RSD is a critical factor for immune cells to develop GC resistance, as it requires 6 days of social defeat to develop, and persists for at least 10 days after stress termination.

“It should be noted that the repeated and chronic nature of RSD is a critical factor for immune cells to develop GC resistance, as it requires 6 days of social defeat to develop, and persists for at least 10 days after stress termination (Avitsur et al, 2002).”

• cites Avitsur et al, 2002 sourceNot checked yet

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May combine two claims.

The consequence of chronic stress is dependent on HPA and sympathetic outflow from the CNS, and stress models differentially affect myeloid cell production depending on how stressors affect these pathways.

“The consequence of chronic stress is dependent on HPA and sympathetic outflow from the CNS, and stress models differentially effect myeloid cell production depending on how stressors affect these pathways.”

May combine two claims.

Microglia are sensitive to the physiological response of stress as they express β-adrenergic and GC receptors, and both stress-induced NE and GCs activate and/or prime microglia to future immune challenges.

“Microglia are sensitive to the physiological response of stress as they express β-adrenergic and GC receptors (Kettenmann et al, 2011).”

• Also stated in: § RSD ACTIVATES STRESS CIRCUITRY, PROMOTES NEUROINFLAMMATION, AND AFFECTS BEHAVIOR · hedged

  “There is a growing literature indicating that both stress-induced NE and GCs activate and/or prime microglia to future immune challenges.”

• cites Kettenmann et al, 2011 sourceNot checked yet

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May combine two claims.

Neuroinflammatory signaling is increased by RSD and is argued to facilitate vulnerability toward mood disorders.

“In addition to activating neuronal fear/anxiety circuitry, neuroinflammatory signaling is increased by RSD (Kinsey et al, 2007;Wohleb et al, 2012) that is argued to facilitate vulnerability toward mood disorders (Haroon et al, 2012).”

• cites Kinsey et al, 2007 sourceNot checked yet

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• cites Wohleb et al, 2012 sourceNot checked yet

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• cites Haroon et al, 2012 sourceNot checked yet

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May combine two claims.

Daily administration of the β-adrenergic antagonist propranolol before social defeat reduced primed and GC-resistant splenetic CD11b+ macrophages and decreased surface expression of TLR2, TLR4, and CD86.

“In support of this, daily administration of the β-adrenergic antagonist propranolol before social defeat reduced primed and GC-resistant splenetic CD11b + macrophages and significantly decreased surface expression of TLR2, TLR4, and CD86 on these cells (Hanke et al, 2012).”

• cites Hanke et al, 2012 sourceNot checked yet

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

Stress levels of NE increase MMP-9 and MMP-2 that increase invasive potential of tumor cells.

“It is known within the cancer literature that stress levels of NE increase MMP-9 and MMP-2 that increase invasive potential of the tumor cells (Sood et al, 2006;Yang et al, 2006).”

• cites Sood et al, 2006 sourceNot checked yet

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• cites Yang et al, 2006 sourceNot checked yet

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May combine two claims.

Peripherally derived Ly6C hi monocytes selectively traffic to CNS threat appraisal centers including the frontal cortex, hypothalamus, amygdala, and hippocampus after 3 cycles and continue to accumulate after 6 cycles.

“peripherally derived Ly6C hi monocytes selectively traffic to CNS threat appraisal centers including the frontal cortex, hypothalamus, amygdala, and hippocampus after 3 cycles and continue to accumulate after 6 cycles.”

May combine two claims.

Stress exposure activates microglia and increases proinflammatory cytokine (IL-1β, TNF-α, IL-6) and chemokine (CCL2) signaling, thereby providing a direct pathway to upregulate adhesion molecules.

“As discussed above, stress exposure activates microglia and increases proinflammatory cytokine (IL-1β, TNF-α, IL-6) and chemokine (CCL2) signaling (Wohleb et al, 2012), thereby providing a direct pathway to upregulate adhesion molecules.”

• cites Wohleb et al, 2012 sourceNot checked yet

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May combine two claims.

Circulating monocytes do not passively diffuse to the brain, but are actively recruited via communication from the CNS.

“Under this view, circulating monocytes do not passively diffuse to the brain, but instead are actively recruited via communication from the CNS.”

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

MMP upregulation and invasiveness of tumor cells were reversed by propranolol treatment.

“Furthermore, MMP upregulation and invasiveness of the tumor cells were reversed by propranolol treatment, highlighting the link between stress hormones and MMPs (Sood et al, 2006).”

• cites Sood et al, 2006 sourceNot checked yet

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May combine two claims.

The CCL2-CCR2 and CX3CL1-CX3CR1 chemotactic axes are two ligand-receptor signaling pathways that recruit monocytes to sites of inflammation, including the brain.

“the CCL2-CCR2 and CX3CL1-CX3CR1 chemotactic axis are two ligand-receptor signaling pathways that recruit monocytes to sites of inflammation (Auffray et al, 2007;Tsou et al, 2007), including the brain (D' Mello et al, 2009).”

• cites Auffray et al, 2007 sourceNot checked yet

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• cites Tsou et al, 2007 sourceNot checked yet

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• cites D' Mello et al, 2009Not checked yet

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May combine two claims.

RSD increased the presence of CD11b+/CD45 high monocyte population in the CNS, and these cells highly expressed Ly6C.

“Here, RSD increased the presence of CD11b + /CD45 high monocyte population in CNS (Wohleb et al, 2011).”

• Also stated in: § RSD-INDUCED PRIMED AND GC-RESISTANT MONOCYTES TRAFFIC TO THE BRAIN TO ELEVATE PROINFLAMMATORY SIGNALING THAT IS ASSOCIATED WITH CHANGES TO BEHAVIOR · plain

  “In addition, these cells highly expressed Ly6C, similar to the expression pattern of circulating monocytes induced by RSD (Powell et al, 2013).”

• cites Wohleb et al, 2011 sourceNot checked yet

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• cites Powell et al, 2013 sourceNot checked yet

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May combine two claims.

The increase of CD11b+/CD45 high persisted despite vascular perfusion, indicating that the monocyte/macrophages adhered to the vasculature or entered the parenchyma.

“It is important to note that the increase of CD11b + /CD45 high persisted despite vascular perfusion, and hence the CD11b + /CD45 high monocyte/macrophages adhered to the vasculature or entered the parenchyma (Wohleb et al, 2012).”

• cites Wohleb et al, 2012 sourceNot checked yet

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May combine two claims.

Proinflammatory gene expression, including IL-1β, is increased after 3 cycles and peaks after 6 cycles in areas of monocyte trafficking.

“proinflammatory gene expression, including IL-1β, is increased after 3 cycles and peaks after 6 cycles in areas of monocyte trafficking”

• cites Wohleb et al, 2013 sourceNot checked yet

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May combine two claims.

Both ICAM and VCAM were increased after 6 days of social defeat that temporally correlated with peripheral monocyte trafficking.

“Both ICAM and VCAM were increased after 6 days of social defeat that temporally correlated with peripheral monocyte trafficking (Sawicki et al, 2015).”

• cites Sawicki et al, 2015 sourceNot checked yet

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May combine two claims.

Peripherally derived monocytes, elevated proinflammatory gene expression, and anxiety-like behavior persist for at least 8 days after the last cycle of social defeat but are no longer apparent after 24 days.

“Peripherally derived monocytes, elevated proinflammatory gene expression, and anxiety-like behavior persist for at least 8 days after the last cycle of social defeat but are no longer apparent after 24 days (Wohleb et al, 2014a)”

• cites Wohleb et al, 2014aNot checked yet

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May combine two claims.

Peripheral monocytes/macrophages highly express IL-1β and retain high expression levels after entering the CNS parenchyma.

“Peripheral monocytes/macrophages highly express IL-1β and retain high expression levels after entering the CNS parenchyma (Ataka et al, 2013).”

• cites Ataka et al, 2013 sourceNot checked yet

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May combine two claims.

Accumulation of Ly6C hi monocytes in circulation begins after 3 cycles and peaks after 6 cycles of social defeat.

“accumulation of Ly6C hi monocytes in circulation begins after 3 cycles and peaks after 6 cycles of social defeat”

• cites Wohleb et al, 2013 sourceNot checked yet

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Classified as probably not a substantial claim.

Monocyte recruitment to the CNS involves dynamic interactions with vascular endothelial cells that comprise the BBB.

“Monocyte recruitment to the CNS involves dynamic interactions with vascular endothelial cells that comprise the BBB.”

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

Leukocyte recruitment to the CNS is a multistep process regulated through expression of adherent surface molecules on leukocytes and endothelial cells.

“Leukocyte recruitment to the CNS is a multistep process that is regulated through expression of adherent surface molecules on leukocytes and endothelial cells (Ransohoff et al, 2003).”

• cites Ransohoff et al, 2003 sourceNot checked yet

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

Chemokine activation of leukocytes initiates relocation and conformational changes to integrins LFA-1 and VLA4 that form high-affinity binding sites for firm adhesion onto endothelial cells.

“Here, chemokine activation of leukocytes initiates relocation and conformational changes to the integrins, lymphocyte function-associated antigen 1 (LFA-1) and very late antigen 4 (VLA4), that form highaffinity binding sites for firm adhesion onto endothelial cells (Kim et al, 2003).”

• cites Kim et al, 2003 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based).

If exposure to stressors such as RSD increases expression of adhesion molecules, this would promote trafficking of circulating immune cells to the CNS.

“Therefore, if exposure to stressors, such as RSD, were to increase expression of adhesion molecules, this would promote trafficking of circulating immune cells to the CNS.”

May combine two claims.

GFP+ monocytes accumulated in the same threat appraisal areas that had increased c-Fos and IBA-1 activation after RSD, but not in other brain regions like the motor cortex or cerebellum, suggesting site-specific recruitment to stress-responsive brain regions.

“Notably, GFP+ monocytes accumulated in the same threat appraisal areas that had increased c-Fos and IBA-1 activation after RSD, but not in other brain regions like the motor cortex or cerebellum, suggesting site-specific recruitment to stress-responsive brain regions (Wohleb et al, 2011(Wohleb et al, , 2013)).”

• cites Wohleb et al, 2011 sourceNot checked yet

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• cites Wohleb et al, 2013 sourceNot checked yet

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May combine two claims.

Under RSD, genetic knockout of CCR2 or CX3CR1 prevented monocyte recruitment to the brain and blocked development of anxiety-like behaviors.

“Under the context of RSD, genetic knockout of CCR2 or CX3CR1 prevented monocyte recruitment to the brain and blocked development of anxiety-like behaviors (Wohleb et al, 2013).”

• cites Wohleb et al, 2013 sourceNot checked yet

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

Dynamic interactions between integrins and CAMs ICAM and VCAM arrest the leukocyte onto the endothelial cell surface.

“Next, dynamic interactions between integrins and the cell adhesion molecules (CAMs), intercellular CAM (ICAM) and vascular CAM (VCAM), arrest the leukocyte onto the endothelial cell surface.”

May combine two claims.

BBB endothelial cells express key cytokine receptors (IL-1R1, IL-6, TNF receptor), and binding of these receptors leads to transport or secretion of additional proinflammatory cytokines and secondary mediators (prostaglandins) that propagate inflammatory signaling into the CNS.

“For instance, BBB endothelial cells express key cytokine receptors (IL-1R1, IL-6, TNF receptor), and binding of these receptors leads to transport or secretion of additional proinflammatory cytokines and secondary mediators (prostaglandins) that propagate inflammatory signaling into the CNS (Bebo and Linthicum, 1995;Ericsson et al, 1995;Vallieres and Rivest, 1999).”

• cites Bebo and Linthicum, 1995 sourceNot checked yet

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• cites Ericsson et al, 1995 sourceNot checked yet

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• cites Vallieres and Rivest, 1999 sourceNot checked yet

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

The first step of leukocyte recruitment involves rolling and capture of leukocytes onto the surface of endothelial cells via enhanced expression of L-selectin and PSGL1 on leukocytes and E- and P-selectin on endothelial cells.

“Typically, the first step involves rolling and capture of leukocytes onto the surface of endothelial cells.This occurs via enhanced expression of the capture molecules, L-selectin and P-selectin glycoprotein ligand 1 (PSGL1) on leukocytes and E-and P-selectin on the luminal surface of endothelial cells.”

May combine two claims.

eIL-1R1 KD reduced proinflammatory cytokine expression in microglia isolated from mice exposed to RSD and prevented RSD-induced anxiety-like behavior.

“However, eIL-1 R 1 KD reduced proinflammatory cytokine expression in microglia isolated from mice exposed to RSD and prevented RSD-induced anxiety-like behavior.”

• cites Li et al, 2011Not checked yet

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May combine two claims.

The pattern of anxiety-like behavior temporally correlates with neuroinflammatory signaling and the presence of peripherally derived monocytes in the brain, as elevated cytokines and monocytes are detected at 8 days but not 24 days after RSD.

“This pattern temporally correlates with neuroinflammatory signaling and the presence of peripherally derived monocytes in the brain, as elevated cytokines and monocytes are detected at 8 days but not 24 days after RSD.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Children might be particularly vulnerable to the ability of chronic stress to reprogram innate immune function, as immune changes can persist throughout the majority of their lifetime.

“Children might be particularly vulnerable to the ability of chronic stress to reprogram innate immune function, as immune changes can persist throughout the majority of their lifetime.”

Probably not a substantial claim: may not pass S1 (asserted), S4 (based).

Initial exposure to RSD causes egress of primed monocyte progenitor cells from the BM that is housed in the spleen.

“a current area of exploration is that initial exposure to RSD causes egress of primed monocyte progenitor cells from the BM that is housed in the spleen.”

May combine two claims.

Identifying CD14+/CD16- monocytes as the primary source of elevated inflammatory gene expression and IL-6 production implicates this cell type as particularly sensitive to chronic stress, and may provide a measurable biomarker to identify vulnerable human subpopulations.

“Identifying CD14 + /CD16 -monocytes as the primary source of elevated inflammatory gene expression and IL-6 production implicates this cell type as particularly sensitive to chronic stress, and may provide a measurable biomarker to identify vulnerable human subpopulations.”

May combine two claims.

Transplantation from an IL-6-deficient mouse, or administration of IL-6 neutralizing antibodies, promoted stress resilience in host mice.

“In opposition, transplantation from an IL-6-deficient mouse, or administration of IL-6 neutralizing antibodies, promoted stress resilience in host mice.”

• cites Hodes et al, 2014 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

This blockade corresponded with reduced microglial cytokine expression and prevented anxiety-like behavior.

“This blockade corresponded with reduced microglial cytokine expression and prevented anxiety-like behavior.”

May combine two claims.

Exposure to subthreshold stress reestablished anxiety-like behavior and reinforced social avoidance.

“Coinciding with reactivation of neuroimmune processes, exposure to subthreshold stress reestablished anxiety-like behavior and reinforced social avoidance.”

May combine two claims.

Within the RSD model, anxiety-like behavior in common behavioral tasks like the open field, light/dark preference, and elevated plus maze occurs immediately after the last cycle of social defeat and persists for at least 8 days, but is no longer apparent after 24 days.

“Within the RSD model, anxiety-like behavior in common behavioral tasks like the open field, light/dark preference, and elevated plus maze occurs immediately after the last cycle of social defeat and persists for at least 8 days, but is no longer apparent after 24 days (Wohleb et al, 2014a).”

• cites Wohleb et al, 2014aNot checked yet

  Not checked in the free run.

May combine two claims.

Childhood adversity promoted clustering of depressive episodes along with elevated circulating IL-6 and CRP.

“Childhood adversity promoted clustering of depressive episodes along with elevated circulating IL-6 and CRP.”

• cites Miller and Cole, 2012 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Stress-sensitized mice with their spleen removed were protected against the effects of stress reexposure to traffic monocytes to the brain and reestablish anxiety-like behaviors.

“Stresssensitized mice with their spleen removed were protected against the effects of stress reexposure to traffic monocytes to the brain and reestablish anxiety-like behaviors (Wohleb et al, 2014a).”

• cites Wohleb et al, 2014aNot checked yet

  Not checked in the free run.

May combine two claims.

Mice with leukocytes that had the largest IL-6 response to LPS before stress produced the most IL-6 after stress and had the largest stress-induced behavioral deficits (social avoidance).

“The mice with leukocytes that had the largest IL-6 response to LPS produced the most IL-6 after stress and had the largest stress-induced behavioral deficits (social avoidance) (Hodes et al, 2014).”

• cites Hodes et al, 2014 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

A single cycle of social defeat is subthreshold because it does not traffic monocytes to the brain, activate microglia, or induce prolonged anxiety-like behavior.

“For example, a single cycle of social defeat is considered to be subthreshold because it does not traffic monocytes to the brain, activates microglia, or induces prolonged anxiety-like behavior.”

Classified as probably not a substantial claim.

The research highlighted illustrates the dual process of GC-resistant/primed monocytes and microglia/endothelial cells in the CNS to converge and promote a heightened neuroinflammatory environment that directly influences the behavioral response to stress.

“The research highlighted above illustrates the dual process of GC-resistant/primed monocytes and microglia/endothelial cells in the CNS to converge and promote a heightened neuroinflammatory environment that directly influences the behavioral response to stress.”

May combine two claims.

CD14+/CD16- monocytes produced higher levels of IL-6 when stimulated with LPS ex vivo, suggesting that similar immune process occur in humans.

“Similar to Ly6C hi monocytes in mice, CD14 + /CD16 -monocytes produced higher levels of IL-6 when stimulated with LPS ex vivo (Miller et al, 2014), suggesting that similar immune process occur in humans.”

• cites Miller et al, 2014 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Inhibiting microglia blunts the stress-induced increase in proinflammatory signaling molecules and subsequent changes to behavior, an effect that is secondary to neuronal activation.

“As already noted, inhibiting microglia blunts the stress-induced increase in proinflammatory signaling molecules and subsequent changes to behavior, an effect that is secondary to neuronal activation.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Each danger signal is not mutually exclusive and likely works in conjunction to promote a heightened neuroinflammatory environment.

“It should be noted that each signal is not mutually exclusive and, in fact, likely works in conjunction to promote a heightened neuroinflammatory environment (Figure 4).”

May combine two claims.

Transplanting the BM from a 'susceptible' mouse to a 'control' mouse promoted susceptibility, with the control mouse having an immune and behavioral phenotype similar to the 'susceptible' donor mouse.

“Interestingly, transplanting the BM from a 'susceptible' mouse to a 'control' mouse promoted susceptibility.That is to say, the control mouse had an immune and behavioral phenotype similar to the 'susceptible' donor mouse.”

• cites Hodes et al, 2014 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The increased CRP in caregivers cannot be attributed to dysregulated GC rhythmicity, as caregivers showed higher cortisol than control subjects 4 h after waking, but did not differ any other time of day.

“This cannot be attributed to dysregulated GC rhythmicity, as caregivers showed higher cortisol than control subjects 4 h after waking, but did not differ any other time of day, indicating that the diurnal secretion of GCs was not affected (Miller et al, 2008).”

• cites Miller et al, 2008 sourceNot checked yet

  Not checked in the free run.

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

Guanethidine is a peripheral sympathetic inhibitor that prevents release of NE.

“For example, guanethidine is a peripheral sympathetic inhibitor that prevents release of NE.”

May combine two claims.

Reexposure to a single cycle of social defeat 24 days after RSD reactivated the neuroimmune axis, leading to increased monocyte trafficking to the brain and elevated proinflammatory cytokine signaling.

“However, reexposure to a single cycle of social defeat 24 days after RSD reactivated the neuroimmune axis, leading to increased monocyte trafficking to the brain and elevated proinflammatory cytokine signaling (Wohleb et al, 2014a;McKim et al, 2015).”

• cites Wohleb et al, 2014aNot checked yet

  Not checked in the free run.

• cites McKim et al, 2015 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Splenetic monocytes are significantly increased following reexposure to subthreshold stress, suggesting that monocytes are newly differentiated from progenitor cells.

“However, splenetic monocytes are significantly increased following reexposure to subthreshold stress, suggesting that monocytes are newly differentiated from progenitor cells.”

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

Similar danger signal processes have been observed in the CNS, including ischemia, and recently, psychological stress.

“This concept originally references peripheral immune processes, such as sterile injury, but similar processes have been observed in the CNS, including ischemia (Liesz et al, 2015), and recently, psychological stress.”

• cites Liesz et al, 2015 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Reestablished anxiety-like behavior, monocyte trafficking to the brain, and microglia cytokine expression were all dependent on an intact spleen.

“Thus, reestablished anxiety-like behavior, monocyte trafficking to the brain, and microglia cytokine expression were all dependent on an intact spleen.”

May combine two claims.

Circulating monocytes from familial caregivers of brain cancer patients showed diminished GR-mediated transcription and heightened NF-κB-mediated transcription associated with an approximately twofold increase of circulating CRP.

“Similar to the RSD rodent model, circulating monocytes from caregivers showed diminished GR-mediated transcription and heightened NF-κBmediated transcription that was associated with an approximately twofold increase of circulating C-reactive protein (CRP).”

• cites Miller et al, 2008 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Danger signals are endogenous signaling molecules that are released in response to 'danger' and activate immune processes to help the organism respond to the adverse event, even in the absence of foreign pathogens.

“Danger signals are endogenous signaling molecules that are released in response to 'danger' and activate immune processes to help the organism respond to the adverse event, even in the absence of foreign pathogens (Matzinger, 2002).”

• cites Matzinger, 2002 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

IL-6 may be a useful biomarker and potential therapeutic target, particularly in treatment-resistant depressive patients.

“As such, IL-6 may be a useful biomarker and potential therapeutic target, particularly in treatment-resistant depressive patients (Hodes et al, 2014).”

• cites Hodes et al, 2014 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

ATP is an activity-dependent signaling molecule that can be released by neurons, astrocytes, and microglia.

“ATP is an activity-dependent signaling molecule that can be released by neurons, astrocytes, and microglia.”

• AssumptionRests on an assumption: ATP is released by neurons, astrocytes, and microglia.

May combine two claims.

HMGB-1 increased NLRP3 mRNA and protein and acts as a priming stimulus for the NLRP3 inflammasome.

“Indeed, HMGB-1 increased NLRP3 mRNA and protein (Xiang et al, 2011;Frank et al, 2015a) and acts as a priming stimulus for the NLRP3 inflammasome (Frank et al, 2015a).”

• cites Xiang et al, 2011 sourceNot checked yet

  Not checked in the free run.

• cites Frank et al, 2015aNot checked yet

  Not checked in the free run.

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

HMGB-1 is a potent proinflammatory signaling molecule that is released under inflammatory conditions, including sepsis and ischemia.

“Past research conducted on peripheral immune cells demonstrates that HMGB-1 is a potent proinflammatory signaling molecule that is released under inflammatory conditions, including sepsis and ischemia (Yang and Tracey, 2009).”

• cites Yang and Tracey, 2009 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

These findings help elucidate the complex communication that occurs in response to stress and highlight novel therapeutic targets to protect against the neuroinflammatory responses that contribute to long-lasting behavioral complications.

“These findings help elucidate the complex communication that occurs in response to stress and highlights novel therapeutic targets to protect against the neuroinflammatory responses that contribute to long-lasting behavioral complications.”

May combine two claims.

Daily treatment with A-804598 during 28 days of chronic unpredictable stress prevented behavioral deficits in sucrose preference, forced swim, and elevated plus maze, suggesting that ATP is necessary for the associated behavioral consequences of stress.

“Furthermore, daily treatment with A-804598 during 28 days of chronic unpredictable stress prevented behavioral deficits in sucrose preference, forced swim, and elevated plus maze, suggesting that ATP is necessary for the associated behavioral consequences of stress.”

May combine two claims.

Astrocytes reside in close proximity to neuronal synapses and express glutamate receptors that regulate Ca2+ influx to influence ATP signaling.

“Astrocytes reside in close proximity to neuronal synapses and express glutamate receptors that regulate CA 2+ influx (Cornell-Bell et al, 1990) to influence ATP signaling (Cotrina et al, 2000).”

• cites Cornell-Bell et al, 1990 sourceNot checked yet

  Not checked in the free run.

• cites Cotrina et al, 2000 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

HMGB-1 primes the NLRP3 inflammasome and exposure to an activating signal, such as ATP, would form the inflammasome complex and cleave pro-IL-β into mature IL-1β, thereby releasing IL-1β.

“Conceptually, HMGB-1 primes the NLRP3 inflammasome and exposure to an activating signal, such as ATP, would form the inflammasome complex and cleave pro-IL-β into mature IL-1β, thereby releasing IL-1β.”

May combine two claims.

HMGB-1 is highly expressed in the CNS and implicated in a variety of neuroinflammatory conditions, including stress.

“Recently, HMGB-1 was found to be highly expressed in the CNS and was implicated in a variety of neuroinflammatory conditions (Kang et al, 2014), including stress (Weber et al, 2015).”

• cites Kang et al, 2014 sourceNot checked yet

  Not checked in the free run.

• cites Weber et al, 2015 sourceNot checked yet

  Not checked in the free run.

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

Repeated stress has been linked with neuronal atrophy in stress-reactive areas including the hippocampus, and hence neurons may also be a significant source of HMGB-1.

“Repeated stress has been linked with neuronal atrophy in stress-reactive areas including the hippocampus (McEwen, 1999), and hence neurons may also be a significant source of HMGB-1.”

• cites McEwen, 1999 sourceNot checked yet

  Not checked in the free run.

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

Caspase-1 requires cleavage from pro-caspase-1 via formation of a multimeric protein complex termed the inflammasome.

“Caspase-1 is also regulated in a similar manner and requires cleavage from pro-caspase-1.This occurs via the formation of a multimeric protein complex termed the inflammasome.”

• cites Martinon et al, 2002 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Receptor targets for HMGB-1 include TLR2 and TLR4 to elicit a proinflammatory response, and RAGE to initiate cell migration and proliferation.

“Receptor targets for HMGB-1 include TLR2 and TLR4 to elicit a proinflammatory response, and the receptor for advanced glycation end products (RAGE) to initiate cell migration and proliferation.”

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

Two separate signals are needed to release IL-1β; the first to drive NLR and pro-IL-1β expression, and the second to form the inflammasome complex and cleave pro-IL-1β to IL-1β.

“Critically, two separate signals are needed to release IL-1β; the first to drive NLR and pro-IL-1β expression, and the second to form the inflammasome complex and cleave pro-IL-1β to IL-1β.”

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

HMGB-1 is a constitutively expressed protein in the nucleus of all cell types, including neurons, astrocytes, and microglia.

“HMGB-1 is a constitutively expressed protein in the nucleus of all cell types, including neurons, astrocytes, and microglia.”

• AssumptionRests on an assumption: HMGB-1 is constitutively expressed in the nucleus of all cell types, including neurons, astrocytes, and microglia.

May combine two claims.

The cellular source of stress-induced ATP likely involves glutamate-mediated neuron-to-astrocyte communication as glutamate was rapidly released before ATP.

“The cellular source of stressinduced ATP likely involves glutamate-mediated neuronto-astrocyte communication as glutamate was rapidly released before ATP.”

May combine two claims.

Stress-induced ATP provides a direct neuron-to-astrocyte-to-microglia communication pathway that enhances IL-1β signaling and affects anxiety-like and depressive-like behaviors.

“Thus, stressinduced ATP provides a direct neuron-to-astrocyte-tomicroglia communication pathway that enhances IL-1β signaling and affects anxiety-like and depressive-like behaviors.”

May combine two claims.

Direct treatment of ATP on primed microglia is sufficient for maturation and release of IL-1β in vitro via the P2X7 receptor expressed on microglia.

“In support of this, direct treatment of ATP on primed microglia is sufficient for maturation and release of IL-1β in vitro (Halle et al, 2008) and does so via the P2X 7 receptor (Colomar et al, 2003) expressed on microglia (Monif et al, 2009).”

• cites Halle et al, 2008 sourceNot checked yet

  Not checked in the free run.

• cites Colomar et al, 2003 sourceNot checked yet

  Not checked in the free run.

• cites Monif et al, 2009 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

HMGB-1 protein is increased in the hippocampus following a series of repeated tail shock and persists for at least 24 h later.

“For example, HMGB-1 protein is increased in the hippocampus following a series of repeated tail shock and persists for at least 24 h later (Weber et al, 2015).”

• cites Weber et al, 2015 sourceNot checked yet

  Not checked in the free run.

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

Neuronal release of HMGB-1 typically occurs during necrotic conditions, such as ischemia and sepsis.

“Typically, neuronal release of HMGB-1 occurs during necrotic conditions, such as ischemia (Yang and Tracey, 2009) and sepsis (Yang et al, 2004).”

• cites Yang and Tracey, 2009 sourceNot checked yet

  Not checked in the free run.

• cites Yang et al, 2004 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

IL-1β is transcribed into the precursor protein pro-IL-1β and requires enzymatic cleavage by caspase-1 into the bioactive and mature IL-1β.

“IL-1β is transcribed into the precursor protein pro-IL-1β and requires enzymatic cleavage by caspase-1 into the bioactive and mature IL-1β.”

• cites Martinon et al, 2002 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Microglia are likely a primary source of stress-induced HMGB-1, as microglia isolated from rats exposed to tail shock actively secreted HMGB-1 in the absence of cell death.

“Microglia are likely a primary source of stress-induced HMGB-1, as microglia isolated from rats exposed to tail shock actively secreted HMGB-1 in the absence of cell death.”

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

The LRR domain on the NLR is sensitive to a diverse array of danger signals, including ATP.

“The LRR domain is sensitive to a diverse array of danger signals, including ATP (Leemans et al, 2011).”

• cites Leemans et al, 2011 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Direct administration of HMGB-1 into the CNS activates NF-κB-dependent transcription, primes the NLRP3 inflammasome, and increases proinflammatory cytokines, including IL-1β.

“Indeed, direct administration of HMGB-1 into the CNS activates NF-κB-dependent transcription, primes the NLRP3 inflammasome, and increases proinflammatory cytokines, including IL-1β (O' Connor et al, 2003a;Yang et al, 2005;Xiang et al, 2011;Frank et al, 2015a).”

• cites O' Connor et al, 2003aNot checked yet

  Not checked in the free run.

• cites Yang et al, 2005 sourceNot checked yet

  Not checked in the free run.

• cites Frank et al, 2015aNot checked yet

  Not checked in the free run.

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

Endothelial cells secrete cytokines and prostaglandins that propagate neuroinflammation.

“In addition, endothelial cells secrete cytokines and prostaglandins that propagate neuroinflammation.”

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

NLRP3 forms a multiprotein complex with ASC and pro-caspase-1 termed the inflammasome.

“In turn, NLRP3 forms a multiprotein complex with ASC and pro-caspase-1 termed the inflammasome.”

• cites [91] Matzinger P (2002). The danger model: a renewed sense of self. Science 296: 301–305. sourceNot checked yet

  Not checked in the free run.

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

Pro-caspase-1 is cleaved to the bioactive caspase-1 that cleaves pro-IL-1β to mature IL-1β.

“Pro-caspase-1 is cleaved to the bioactive caspase-1 that cleaves pro-IL-1β to mature IL-1β.”

• cites [91] Matzinger P (2002). The danger model: a renewed sense of self. Science 296: 301–305. sourceNot checked yet

  Not checked in the free run.

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

HMGB-1 primes the NLRP3 inflammasome in the CNS after stress exposure.

“First evidence that HMGB-1 primes the NLRP3 inflammasome in the CNS after stress exposure.”

• cites [138] Wohleb ES, Fenn AM, Pacenta AM, Powell ND, Sheridan JF, Godbout JP (2012). Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice. Psychoneuroendocrinology 37: 1491–1505. sourceNot checked yet

  Not checked in the free run.

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

The inflammasome complex mediates caspase-1 activation.

“A seminal article that identified the inflammasome complex as the mediator of caspase-1activation.”

• cites [91] Matzinger P (2002). The danger model: a renewed sense of self. Science 296: 301–305. sourceNot checked yet

  Not checked in the free run.

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

Childhood adversity promotes clustering of depressive episodes along with elevated circulating IL-6 and CRP.

“Childhood adversity promotes clustering of depressive episodes along with elevated circulating IL-6 and CRP”

• cites [100] Miller GE, Murphy ML, Cashman R, Ma R, Ma J, Arevalo JM et al (2014). Greater inflammatory activity and blunted glucocorticoid signaling in monocytes of chronically stressed caregivers. Brain Behav Immun 41: 191–199. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

Rolling/capture occurs via PSGL-1/P-selectin and L-selectin/E-selectin interactions.

“Rolling/capture occurs via PSGL-1/P-selectin and L-selectin/E-selectin interactions.”

May combine two claims.

HMGB1 signals through Toll-like receptors to translocate NF-κB to the nucleus that drives transcription of pro-IL-1β and NLRP3.

“HMGB1 signals through Toll-like receptors to translocate NF-κB to the nucleus that drives transcription of pro-IL-1β and NLRP3.”

• cites [42] Frank MG, Weber MD, Fonken LK, Hershman SA, Watkins LR, Maier SF (2015a). The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and microglial priming: a role for the NLRP3 inflammasome. Brain Behav Immun 55: 215–224. sourceNot checked yet

  Not checked in the free run.

• cites [43] Frank MG, Weber MD, Watkins LR, Maier SF (2015b). Stress sounds the alarmin: the role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming. Brain Behav Immun 48: 1–7. sourceNot checked yet

  Not checked in the free run.

• cites [138] Wohleb ES, Fenn AM, Pacenta AM, Powell ND, Sheridan JF, Godbout JP (2012). Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice. Psychoneuroendocrinology 37: 1491–1505. sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Adhesion molecules that recruit leukocytes are increased in brain vasculature after social defeat in an exposure- and brain region-dependent manner.

“Adhesion molecules that recruit leukocytes are increased in brain vasculature after social defeat in an exposure-and brain region-dependent manner.”