Disruption of microglia histone acetylation and protein pathways in mice exhibiting inflammation-associated depression-like symptoms

Rodriguez-Zas, Sandra L.; Wu, Cong; Southey, Bruce R.; O’Connor, Jason C.; Nixon, Scott E.; Garcia, Robmay; Zavala, Cynthia; Lawson, Marcus A.; McCusker, Robert H.; Romanova, Elena V.; Sweedler, Jonathan V.; Kelley, Keith W.; Dantzer, Robert

doi:10.1016/j.psyneuen.2018.06.024

Cited by 21 publications

(12 citation statements)

References 68 publications

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“…Rodriguez-Zas reported an association between indoleamine-pyrrole 2,3 dioxygenase 1 (IDO1) deficiency and phagocytosis and, additionally, immune challenges such as Bacille Calmette-Guerin activation of neurotoxic metabolite microglia phagocytic pathways might induce neurodegeneration and depression-like behavior. [28] Our results showed there were 2 hub genes ( PSMD2 and PSMD6 ) associated with Epstein-Barr virus infection. Ford [29] suggested depressive symptoms are linked to Epstein-Barr virus reactivation among Epstein-Barr virus positive female adolescents, but not males.…”

Section: Discussionmentioning

confidence: 82%

Umbilical cord blood-based gene signatures related to prenatal major depressive disorder: Retracted

Liu

Zhang

Zheng³

et al. 2019

Medicine

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Section: Discussionmentioning

confidence: 82%

Umbilical cord blood-based gene signatures related to prenatal major depressive disorder: Retracted

Liu

Zhang

Zheng³

et al. 2019

Medicine

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“…Histone H2A plays a role in many cell activities such as gene silencing, cell cycle regulation, fatty acid metabolism and apoptosis [27]. Sandra found that Histone H2A was significantly up-regulated in Bacille Calmette-Guerin (BCG)-inoculated mice, indicating that Histone H2A plays a crucial role in inflammation [28]. Nakata found that heat shock could significantly increase the expression of Histone H2A in Hela cells [29].…”

Section: Discussionmentioning

confidence: 99%

Proteomic study of hypothalamus in pigs exposed to heat stress

Yong

et al. 2020

BMC Vet Res

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Background: With evidence of warming climates, it is important to understand the effects of heat stress in farm animals in order to minimize production losses. Studying the changes in the brain proteome induced by heat stress may aid in understanding how heat stress affects brain function. The hypothalamus is a critical region in the brain that controls the pituitary gland, which is responsible for the secretion of several important hormones. In this study, we examined the hypothalamic protein profile of 10 pigs (15 ± 1 kg body weight), with five subjected to heat stress (35 ± 1°C; relative humidity = 90%) and five acting as controls (28 ± 3°C; RH = 90%). Result: The isobaric tags for relative and absolute quantification (iTRAQ) analysis of the hypothalamus identified 1710 peptides corresponding to 360 proteins, including 295 differentially expressed proteins (DEPs), 148 of which were up-regulated and 147 down-regulated, in heat-stressed animals. The Ingenuity Pathway Analysis (IPA) software predicted 30 canonical pathways, four functional groups, and four regulatory networks of interest. The DEPs were mainly concentrated in the cytoskeleton of the pig hypothalamus during heat stress. Conclusions: In this study, heat stress significantly increased the body temperature and reduced daily gain of body weight in pigs. Furthermore, we identified 295 differentially expressed proteins, 147 of which were down-regulated and 148 up-regulated in hypothalamus of heat stressed pigs. The IPA showed that the DEPs identified in the study are involved in cell death and survival, cellular assembly and organization, and cellular function and maintenance, in relation to neurological disease, metabolic disease, immunological disease, inflammatory disease, and inflammatory response. We hypothesize that a malfunction of the hypothalamus may destroy the host physical and immune function, resulting in decreased growth performance and immunosuppression in heat stressed pigs.

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“…In contrast to neurons, astrocytes have been shown to be resistant to apoptosis-induced bystander killing via the Fas-ligand [ 44 ], thus reminding us of the potential to limit the bystander effect via glia. Phagocytes rapidly remove unhealthy cells and debris from damaged tissue to prevent the uncontrolled release of cytokines and inflammation, which has been shown to have a beneficial effect on prolonged social withdrawal, resignation, and anhedonia [ 45 ]. Our data showed that in response to TBI, astrocytes changed to a phenotype with prolonged processes and hypertrophic bodies at 3 and 7 dpi (Fig.…”

Section: Discussionmentioning

confidence: 99%

AXL kinase-mediated astrocytic phagocytosis modulates outcomes of traumatic brain injury

Zhou

et al. 2021

J Neuroinflammation

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Background Complex changes in the brain microenvironment following traumatic brain injury (TBI) can cause neurological impairments for which there are few efficacious therapeutic interventions. The reactivity of astrocytes is one of the keys to microenvironmental changes, such as neuroinflammation, but its role and the molecular mechanisms that underpin it remain unclear. Methods Male C57BL/6J mice were subjected to the controlled cortical impact (CCI) to develop a TBI model. The specific ligand of AXL receptor tyrosine kinase (AXL), recombinant mouse growth arrest-specific 6 (rmGas6) was intracerebroventricularly administered, and selective AXL antagonist R428 was intraperitoneally applied at 30 min post-modeling separately. Post-TBI assessments included neurobehavioral assessments, transmission electron microscopy, immunohistochemistry, and western blotting. Real-time polymerase chain reaction (RT-PCR), siRNA transfection, and flow cytometry were performed for mechanism assessments in primary cultured astrocytes. Results AXL is upregulated mainly in astrocytes after TBI and promotes astrocytes switching to a phenotype that exhibits the capability of ingesting degenerated neurons or debris. As a result, this astrocytic transformation promotes the limitation of neuroinflammation and recovery of neurological dysfunction. Pharmacological inhibition of AXL in astrocytes significantly decreased astrocytic phagocytosis both in vivo and in primary astrocyte cultures, in contrast to the effect of treatment with the rmGas6. AXL activates the signal transducer and activator of the transcription 1 (STAT1) pathway thereby further upregulating ATP-binding cassette transporter 1 (ABCA1). Moreover, the supernatant from GAS6-depleted BV2 cells induced limited enhancement of astrocytic phagocytosis in vitro. Conclusion Our work establishes the role of AXL in the transformation of astrocytes to a phagocytic phenotype via the AXL/STAT1/ABCA1 pathway which contributes to the separation of healthy brain tissue from injury-induced cell debris, further ameliorating neuroinflammation and neurological impairments after TBI. Collectively, our findings provide a potential therapeutic target for TBI.

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Disruption of microglia histone acetylation and protein pathways in mice exhibiting inflammation-associated depression-like symptoms

Cited by 21 publications

References 68 publications

Umbilical cord blood-based gene signatures related to prenatal major depressive disorder: Retracted

Umbilical cord blood-based gene signatures related to prenatal major depressive disorder: Retracted

Proteomic study of hypothalamus in pigs exposed to heat stress

AXL kinase-mediated astrocytic phagocytosis modulates outcomes of traumatic brain injury

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