Glucocorticoid Activation of Anti-Inflammatory Macrophages in Coordination with STAT6 Protects Against Insulin Resistance and Maintains Homeothermy

Caratti, Giorgio; Stifel, Ulrich; Caratti, Bozhena; Chung, Kyoung‐Jin; Kiehntopf, Michael; Blüher, Matthias; Rauch, Alexander; Tuckermann, Jan

doi:10.2139/ssrn.3713506

Cited by 4 publications

(4 citation statements)

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“…In the presence of macrophages, treatment with Dex significantly upregulated the transcription levels of osteogenic genes in BSMPs (e.g., Sp7) and CMPs on day 3 and increased the ALP-positive area on day 5 (Supplemental Figure 10, A and B). Consistent with previous findings that GCs induce polarization of macrophages into an M2-like phenotype (1,31), we also identified increased expression of Cd163, Cd204, Arg1, IL10, Tgfb, IL4, and BMP2, and decreased expression of IL6, IL1, and Tnfa (Supplemental Figure 10C). Conditioned medium from macrophages pretreated with high-dose Dex significantly upregulated the transcription of osteogenic genes (Supplemental Figure 10D).…”

Section: Resultssupporting

confidence: 92%

Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment

Li,

Liang,

Dai

et al. 2024

Journal of Clinical Investigation

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Elevated bone resorption and diminished bone formation have been recognized as the primary features of glucocorticoid-associated skeletal disorders. However, the direct effects of excess glucocorticoids on bone turnover remain unclear. Here, we explored the outcomes of exogenous glucocorticoid treatment on bone loss and delayed fracture healing in mice and found that reduced bone turnover was a dominant feature, resulting in a net loss of bone mass. The primary effect of glucocorticoids on osteogenic differentiation was not inhibitory; instead, they cooperated with macrophages to facilitate osteogenesis. Impaired local nutrient status — notably, obstructed fatty acid transportation — was a key factor contributing to glucocorticoid-induced impairment of bone turnover in vivo. Furthermore, fatty acid oxidation in macrophages fueled the ability of glucocorticoid-liganded receptors to enter the nucleus and then promoted the expression of BMP2 , a key cytokine that facilitates osteogenesis. Metabolic reprogramming by localized fatty acid delivery partly rescued glucocorticoid-induced pathology by restoring a healthier immune-metabolic milieu. These data provide insights into the multifactorial metabolic mechanisms by which glucocorticoids generate skeletal disorders, thus suggesting possible therapeutic avenues.

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Section: Resultssupporting

confidence: 92%

Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment

Li,

Liang,

Dai

et al. 2024

Journal of Clinical Investigation

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“…Some of these scenarios have already been modeled in vitro 39, 61, 62, 63 . In our transcriptomic studies, a small subset of genes (n=41) were regulated by IL4 and Dex in opposite directions, implying a potential antagonism, whereas the rest of the shared genes may display additive or synergistic relationship, as has been recently proposed 64 . Our DSS-colitis model suggests that the defective tissue repair function of GRIP1 cKO macrophages rather than the uncontrolled inflammation was a dominant contributor to the phenotype at the end-stage of the disease.…”

Section: Discussionsupporting

confidence: 59%

Mechanisms of Epigenomic and Functional Convergence Between Glucocorticoid and IL4-Driven Macrophage Programming

Deochand,

Dacic,

Bale

et al. 2024

Preprint

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Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids, widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2GC), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics that M2IL4 and M2GC transcriptomes share a striking overlap mirrored by a shift in chromatin landscape in both common and signal-specific gene subsets. This core homeostatic program is enacted by transcriptional effectors KLF4 and the GC receptor, whose genome-wide occupancy and actions are integrated in a stimulus-specific manner by the nuclear receptor cofactor GRIP1. Indeed, many of the M2IL4:M2GC-shared transcriptomic changes were GRIP1-dependent. Consistently, GRIP1 loss attenuated phagocytic activity of both populations in vitro and macrophage tissue-repair properties in the murine colitis model in vivo. These findings provide a mechanistic framework for homeostatic macrophage programming by distinct signals, to better inform anti-inflammatory drug design.

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“…Since glucocorticoid signals through glucocorticoid receptor (GR) to mediate immunoregulatory functions, we hypothesized that glucocorticoid-GR interaction may reinforce the antisteroidogenic Trem2-TGFβ pathway. Notably, according to a recent RNA sequencing study, GR -/-MФ exhibited substantial downregulation of Trem2 at baseline than WT control (72) (Supplemental Figure 9A), suggesting GR may drive Trem2 transcription in AG MФ. To test this hypothesis experimentally, RU486 (mifepristone) was used to antagonize GR in BV2 cells.…”

Section: Glucocorticoid Receptor Enhances Trem2-tgfβ Axis To Reinforc...mentioning

confidence: 81%

Adrenal gland macrophages regulate glucocorticoid production through Trem2 and TGF-β

Xu,

Patterson,

Dolfi

et al. 2024

JCI Insight

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Glucocorticoid synthesis by adrenal glands (AGs) is regulated by the hypothalamic-pituitary-adrenal axis to facilitate stress responses when the host is exposed to stimuli. Recent studies implicate macrophages as potential steroidogenic regulators, but the molecular mechanisms by which AG macrophages exert such influence remain unclear. In this study, we investigated the role of AG macrophages in response to cold challenge or atherosclerotic inflammation as physiologic models of acute or chronic stress. Using single-cell RNA sequencing, we observed dynamic AG macrophage polarization toward classical activation and lipid-associated phenotypes following acute or chronic stimulation. Among transcriptional alterations induced in macrophages, triggering receptor expressed on myeloid cells 2 (Trem2) was highlighted because of its upregulation following stress. Conditional deletion of macrophage Trem2 revealed a protective role in stress responses. Mechanistically, Trem2 deletion led to increased AG macrophage death, abolished the TGF-β–producing capacity of AG macrophages, and resulted in enhanced glucocorticoid production. In addition, enhanced glucocorticoid production was replicated by blockade of TGF-β signaling. Together, these observations suggest that AG macrophages restrict steroidogenesis through Trem2 and TGF-β, which opens potential avenues for immunotherapeutic interventions to resolve stress-related disorders.

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Glucocorticoid Activation of Anti-Inflammatory Macrophages in Coordination with STAT6 Protects Against Insulin Resistance and Maintains Homeothermy

Cited by 4 publications

References 0 publications

Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment

Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment

Mechanisms of Epigenomic and Functional Convergence Between Glucocorticoid and IL4-Driven Macrophage Programming

Adrenal gland macrophages regulate glucocorticoid production through Trem2 and TGF-β

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