Fighting the Fire: Mechanisms of Inflammatory Gene Regulation by the Glucocorticoid Receptor

Escoter-Torres, Laura; Caratti, Giorgio; Mechtidou, Aikaterini; Tuckermann, Jan; Uhlenhaut, N. Henriette; Vettorazzi, Sabine

doi:10.3389/fimmu.2019.01859

Cited by 108 publications

(92 citation statements)

References 222 publications

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“…NR3C1 usually exists in the cytoplasm and would be translocated to the nucleus after binding to its ligand. It could upregulate the anti-inflammatory protein or inhibit the expression of pro-inflammatory protein in the nucleus 59 . The significant downregulation of NR3C1 in the five organs may indicate an increased inflammatory response of various organs after SARS-CoV-2 infection.…”

Section: Cluster 4: Cytokinesmentioning

confidence: 99%

Multi-organ Proteomic Landscape of COVID-19 Autopsies

Nie¹,

Qian²,

Sun³

et al. 2020

Preprint

149

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The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report an in-depth multi-organ proteomic landscape of COVID-19 patient autopsy samples. By integrative analysis of proteomes of seven organs, namely lung, spleen, liver, heart, kidney, thyroid and testis, we characterized 11,394 proteins, in which 5336 were perturbed in COVID-19 patients compared to controls. Our data showed that CTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. Dysregulation of protein translation, glucose metabolism, fatty acid metabolism was detected in multiple organs. Our data suggested upon SARS-CoV-2 infection, hyperinflammation might be triggered which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart and thyroid. Evidence for testicular injuries included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. In summary, this study depicts the multi-organ proteomic landscape of COVID-19 autopsies, and uncovered dysregulated proteins and biological processes, offering novel therapeutic clues.

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Section: Cluster 4: Cytokinesmentioning

confidence: 99%

Multi-organ Proteomic Landscape of COVID-19 Autopsies

Nie¹,

Qian²,

Sun³

et al. 2020

Preprint

149

View full text Add to dashboard Cite

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“…Thus, it is possible that induction of Epo expression contributes to the resolution of inflammation. Similarly, increased levels of corticosteroids play an essential role in stress erythropoiesis, but glucocorticoid receptor signaling is also a potent anti-inflammatory signal [116]. Thus, Epo and corticosteroids represent signals that drive the proliferation and differentiation of SEPs and promote the resolution of inflammation.…”

Section: New Model: Stress Erythropoiesis Is a Key Component Of The Imentioning

confidence: 99%

Stress Erythropoiesis is a Key Inflammatory Response

Paulson

Ruan

et al. 2020

Cells

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Bone marrow medullary erythropoiesis is primarily homeostatic. It produces new erythrocytes at a constant rate, which is balanced by the turnover of senescent erythrocytes by macrophages in the spleen. Despite the enormous capacity of the bone marrow to produce erythrocytes, there are times when it is unable to keep pace with erythroid demand. At these times stress erythropoiesis predominates. Stress erythropoiesis generates a large bolus of new erythrocytes to maintain homeostasis until steady state erythropoiesis can resume. In this review, we outline the mechanistic differences between stress erythropoiesis and steady state erythropoiesis and show that their responses to inflammation are complementary. We propose a new hypothesis that stress erythropoiesis is induced by inflammation and plays a key role in maintaining erythroid homeostasis during inflammatory responses.

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“…Previous studies showed that Sp1, Egr-1, NFKB1, NR3C1 and PU.1 have been reported to play roles in inflammatory response [30][31][32][33][34], so we analyzed the mRNA levels of these transcription factors and found that, compared with those in control group, the mRNA levels of NFKB1, NR3C1 and Egr-1 were obviously lower in ALI group, while the mRNA levels of Sp1 and PU.1 significantly increased ( Figure 7E, P<0.05). Because the luciferase activity results showed that the putative transcription factors could negatively regulate MAPK4 expression and accumulating evidences have shown that NFKB1 and NR3C1 were anti-inflammatory genes [31,32], so we presumed that NFKB1 and NR3C1 might be critical transcription factors in regulating MAPK4 expression in ALI. Expectedly, further analysis showed that the protein levels of NFKB1 and NR3C1 decreased obviously in lung tissues in ALI mice ( Figure 7F, P<0.05), which is consistent with our above data.…”

Section: Nfkb1 and Nr3c1 Negatively Regulate The Expression Of Mapk4mentioning

confidence: 83%

NFKB1/NR3C1-MAPK4 axis regulates the pathology of acute lung injury

Mao

Zhou

et al. 2020

Preprint

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BackgroundAcute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. MAPK4, a member of atypical MAPK family, has been implicated in the development of cancer. Herein, the current study aimed to investigate the possible role of MAPK4 in the pathology of ALI to identify potential candidates for ALI therapy. MethodsMurine ALI model was established in WT or MAPK4 -/mice and the expressions of MAPK4 were measured. The survival ratio of ALI model mice was observed. Moreover, the changes of pathologic injury and infiltration of inflammatory cells, as well as the related signaling pathways, in lung tissues were analyzed. Furthermore, the possible molecular mechanism of MAPK4 expression in ALI was analyzed by massARRAY and EMSA assay. Finally, the effect of MAPK4 silencing using shRNA interference on the pathology of ALI was identified. the expression of MAPK4 by binding to the core sequence of MAPK4 promoter. Importantly, MAPK4-shRNA treatment could significantly reduce the pathology of lung tissues and prolong survival time of ALI mice. Altogether, our study reveals an unknown role of MAPK4 in the pathology of ALI, indicating that MAPK4 might be a new therapeutic target for clinic therapy against ALI. Materials And MethodsMice MAPK4 deficiency (MAPK4 -/-) mice breeding pair in a C57BL/6 background were purchased from The Jackson Laboratory (027666). Animals were housed under specific pathogen-free conditions at Zunyi Medical University. Cell cultureRaw264.7 cells were purchased from Conservation Genetics CAS Kunming Cell Bank (KCB200603YJ), and were cultured in high glucose DEME containing 10% fetal bovine serum at 37°C in 5% CO 2 . Establishment of ALI ModelWT and MAPK4 -/mice (7 to 9 week-old) were challenged with i.p. injection of 10mg/kg LPS (Escherichia coli 0111:B4; Sigma) dissolved in sterile PBS as shown in our previous study [17]. Then the body weight and lung weight index (lung weight/body weight) was detected at indicated time. Bronchoalveolar LavageImmediately after euthanasia, 1 ml aliquots of PBS were slowly infused in the murine lungs through the tracheostomy and then withdrawn gently. This lavage was repeated three times using the same syringe. The collected lavage fluid was stored in a 10ml tube on ice. The fluid was centrifuged at 1000rpm and 4°C for 10 min, and the cell sediment was washed with PBS. The cell-free supernatant was centrifuged again at 14,000g and 4°C for 10 min, stored at −80°C and used for determination of cytokines content via ELISA. To the pellet, red blood lysis buffer (Solarbio, R1010) were used for 15 min and washed with PBS. Next, the pellet was resuspended for analysis. Lung edema determinationLungs from mice were excised and completely dried in the oven at 60°C 24h for calculation of lung wet/dry ratio.

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Fighting the Fire: Mechanisms of Inflammatory Gene Regulation by the Glucocorticoid Receptor

Cited by 108 publications

References 222 publications

Multi-organ Proteomic Landscape of COVID-19 Autopsies

Multi-organ Proteomic Landscape of COVID-19 Autopsies

Stress Erythropoiesis is a Key Inflammatory Response

NFKB1/NR3C1-MAPK4 axis regulates the pathology of acute lung injury

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