Glucocorticoids as Regulators of Macrophage-Mediated Tissue Homeostasis

Díaz-Jiménez, David; Kolb, Joseph P.; Cidlowski, John A.

doi:10.3389/fimmu.2021.669891

Cited by 32 publications

(23 citation statements)

References 132 publications

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“…However, acute stress, such as 3 h of immobilization stress, can induce an increase in corticosterone, resulting in increased neurogenesis in the dentate gyrus of rats [ 46 ]. During neurogenesis in the dentate gyrus, stress-induced corticosterone activates microglia to maintain homeostasis of neurogenesis in the hippocampus [ 47 ]. Moreover, microglia can induce factors to modulate neural proliferation and survival [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Acute stress induces severe neural inflammation and overactivation of glucocorticoid signaling in interleukin-18-deficient mice

Yamanishi

Doe²,

Mukai³

et al. 2022

Transl Psychiatry

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Interleukin-18 (IL18) is an inflammatory cytokine that is related to psychiatric disorders such as depression and cognitive impairment. We previously found that IL18 deficiency may cause hippocampal impairment, resulting in depression-like behavioral changes. However, the potential role of IL18 in stressful conditions remains uncertain. In the present study, we examined the effect of IL18 on neural inflammation and stress tolerance during acute stress. Littermate Il18+/+ and Il18−/− mice were exposed to a single restraint stress for 6 h, and all assessments were performed 18 h after the mice were released from the restraint. In Il18−/− mice exposed to acute stress, the immobility times in both the forced swim test and tail suspension test were decreased, although no difference was observed in Il18+/+ mice. Il1β, Il6, and Tnfα expression levels in the hippocampus of stressed Il18−/− mice were significantly higher than those in the other groups. Moreover, the numbers of astrocytes and microglia, including those in the active form, were also increased compared with those in other groups. Regarding the molecular mechanism, the HSF5 and TTR genes were specifically expressed in stressed Il18−/− mice. As a potential treatment, intracerebral administration of IL18 to Il18−/− mice resulted in partial recovery of changes in behavioral assessments. Our results revealed that IL18-deficient mice were more sensitive and had a longer response to acute stress than that in normal mice. In addition, neural inflammation and augmentation of glucocorticoid signals caused by stress were more intense and remained longer in Il18−/− mice, resulting in behavioral changes. In conclusion, IL18 might be an indispensable factor that modulates the stress response and maintains balance between neural inflammation and glucocorticoid signaling.

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Section: Discussionmentioning

confidence: 99%

Acute stress induces severe neural inflammation and overactivation of glucocorticoid signaling in interleukin-18-deficient mice

Yamanishi

Doe²,

Mukai³

et al. 2022

Transl Psychiatry

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“…When brain homeostasis is disrupted due to brain injury or chronic stress, the CNS has endogenous defense mechanisms that promote tissue repair. Various anti-inflammatory cytokines, growth factors, and hormones, such as glucocorticoids, are released by injured neurons and promote surrounding microglia to transform into an M2-like protective phenotype [58,59]. M2 microglia can be activated by four main anti-inflammatory cytokines, IL-4, IL-10, IL-13, and TGF-β.…”

Section: Microglia Activation and Polarizationmentioning

confidence: 99%

Microglia Phenotypes in Aging and Neurodegenerative Diseases

Wendimu

Hooks

2022

Cells

144

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Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development. This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimer’s disease (AD), and Parkinson’s disease (PD). The primary focus is translational research in preclinical animal models and bulk/single-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.

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“…One important factor that these therapeutic approaches will have to consider in the context of ACC, is the presence of high levels of glucocorticoids produced by adrenal steroidogenic cells, in particular within hormonally active tumours. Although glucocorticoids do not have the same detrimental impact on macrophages that they have on lymphocytes, they are generally associated with M2like tolerogenic differentiation 54 . Therefore, therapeutics targeting macrophages in ACC, should probably consider combining macrophage activation with inhibition of glucocorticoid production or signalling, which would also favour recruitment of adaptive immune cells to the lesion.…”

Section: Discussionmentioning

confidence: 99%

Sexually dimorphic activation of innate antitumour immunity prevents adrenocortical carcinoma development

Wilmouth

Olabe

Garcia-Garcia

et al. 2022

Preprint

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SummaryIn contrast with most cancers, adrenocortical carcinomas (ACC) are more frequent in women than men, but the underlying mechanisms of this sexual dimorphism remain elusive. Homozygous deletion of the negative WNT pathway regulator ZNRF3 is the most frequent alteration in ACC patients. Here, we show that Cre-mediated inactivation of Znrf3 in steroidogenic cells of the mouse adrenal cortex is associated with sexually dimorphic tumour progression. Indeed, although most knockout female mice develop metastatic carcinomas over an 18 month-time course, adrenal hyperplasia gradually regresses in male knockout mice. This male-specific regression is associated with induction of senescence and recruitment of macrophages, which differentiate as active phagocytes that clear-out senescent preneoplastic cells. Macrophage recruitment is also observed in female mice. However, it is delayed and dampened compared to males, which allows for tumour progression. Interestingly, testosterone treatment of female knockouts is sufficient to induce senescence, recruitment of phagocytic macrophages and regression of hyperplasia. We further show that although macrophages are present within adrenal tumours at 18 months, MERTKhigh active phagocytes are mostly found in indolent lesions in males but not in aggressive tumours in females. Consistent with our observations in mice, analysis of RNA sequencing data from the TCGA cohort of ACC shows that phagocytic macrophages are more prominent in men than women and associated with better prognosis. Altogether, these data establish that phagocytic macrophages prevent aggressive ACC development in male mice and suggest that they may play a key role in the unusual sexual dimorphism of ACC in patients.

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Glucocorticoids as Regulators of Macrophage-Mediated Tissue Homeostasis

Cited by 32 publications

References 132 publications

Acute stress induces severe neural inflammation and overactivation of glucocorticoid signaling in interleukin-18-deficient mice

Acute stress induces severe neural inflammation and overactivation of glucocorticoid signaling in interleukin-18-deficient mice

Microglia Phenotypes in Aging and Neurodegenerative Diseases

Sexually dimorphic activation of innate antitumour immunity prevents adrenocortical carcinoma development

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