Amphiregulin Aggravates Glomerulonephritis via Recruitment and Activation of Myeloid Cells

Melderis, Simon; Hagenstein, Julia; Warkotsch, Matthias T.; Dang, Julien; Herrnstadt, Georg R.; Niehus, Christoph B.; Neumann, Katrin; Panzer, Ulf; Berasain, Carmen; Avila, Matı́as A.; Tharaux, Pierre‐Louis; Tiegs, Gisa; Steinmetz, Oliver M.

doi:10.1681/asn.2019111215

Cited by 14 publications

(12 citation statements)

References 56 publications

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“…7 ). However, since Areg is produced not only from Tregs but also from various types of cells, 53 we cannot conclude that Areg is an essential factor for kidney Tregs.…”

Section: Discussionmentioning

confidence: 87%

Kidney GATA3+ regulatory T cells play roles in the convalescence stage after antibody-mediated renal injury

et al. 2020

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FoxP3+ regulatory T cells (Tregs) play crucial roles in peripheral immune tolerance. In addition, Tregs that reside or accumulate in nonlymphoid tissues, called tissue Tregs, exhibit tissue-specific functions and contribute to the maintenance of tissue homeostasis and repair. In an experimental mouse model of crescentic glomerulonephritis induced by an anti-glomerular basement membrane antibody, Tregs started to accumulate in the kidney on day 10 of disease onset and remained at high levels (~30–35% of CD4+ T cells) during the late stage (days 21–90), which correlated with stable disease control. Treg depletion on day 21 resulted in the relapse of renal dysfunction and an increase in Th1 cells, suggesting that Tregs are essential for disease control during the convalescence stage. The Tregs that accumulated in the kidney showed tissue Treg phenotypes, including high expression of GATA3, ST2 (the IL33 receptor subunit), amphiregulin (Areg), and PPARγ. Although T-bet+ Tregs and RORγt+ Tregs were observed in the kidney, GATA3+ Tregs were predominant during the convalescence stage, and a PPARγ agonist enhanced the accumulation of GATA3+ Tregs in the kidney. To understand the function of specific genes in kidney Tregs, we developed a novel T cell transfer system to T cell-deficient mice. This experiment demonstrates that ST2, Areg, and CCR4 in Tregs play important roles in the accumulation of GATA3+ Tregs in the kidney and in the amelioration of renal injury. Our data suggest that GATA3 is important for the recruitment of Tregs into the kidney, which is necessary for convalescence after renal tissue destruction.

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“…7 ). However, since Areg is produced not only from Tregs but also from various types of cells, 53 we cannot conclude that Areg is an essential factor for kidney Tregs.…”

Section: Discussionmentioning

confidence: 87%

Kidney GATA3+ regulatory T cells play roles in the convalescence stage after antibody-mediated renal injury

et al. 2020

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“…AREG expression is mainly elevated in pathological conditions, such as cirrhosis ( Perugorria et al, 2008 ) and chronic obstructive pulmonary disease ( Val et al, 2012 ). Recent studies on mouse models of glomerulonephritis also showed that AREG can enhance the function of Treg cells, inhibit the growth of CD4 + T cells, and promote the recruitment of myeloid cells, proliferation, and cytokine secretion of M1 cells ( Melderis et al, 2020 ). The increase in AREG in patients with TARSM might serve as an activation signal for monocytes.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell RNA Sequencing Revealed CD14+ Monocytes Increased in Patients With Takayasu’s Arteritis Requiring Surgical Management

Gao

Wu²,

Yu³

et al. 2021

Front. Cell Dev. Biol.

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Objectives: Takayasu Arteritis (TA) is a highly specific vascular inflammation and poses threat to patients’ health. Although some patients have accepted medical treatment, their culprit lesions require surgical management (TARSM). This study aimed at dissecting the transcriptomes of peripheral blood mononuclear cells (PBMCs) in these patients and to explore potential clinical markers for TA development and progression.Methods: Peripheral blood were collected from four TA patients requiring surgical management and four age-sex matched healthy donors. Single cell RNA sequencing (scRNA-seq) was adopted to explore the transcriptomic diversity and function of their PBMCs. ELISA, qPCR, and FACS were conducted to validate the results of the analysis.Results: A total of 29918 qualified cells were included for downstream analysis. Nine major cell types were confirmed, including CD14+ monocytes, CD8+ T cells, NK cells, CD4+ T cells, B cells, CD16+ monocytes, megakaryocytes, dendritic cells and plasmacytoid dendritic cells. CD14+ monocytes (50.0 vs. 39.3%, p < 0.05) increased in TA patients, as validated by FACS results. TXNIP, AREG, THBS1, and CD163 increased in TA patients. ILs like IL-6, IL-6STP1, IL-6ST, IL-15, and IL-15RA increased in TA group.Conclusion: Transcriptome heterogeneities of PBMCs in TA patients requiring surgical management were revealed in the present study. In the patients with TA, CD14+ monocytes and gene expressions involved in oxidative stress were increased, indicating a new treatment and research direction in this field.

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“…In our study, acute phase DCS was accompanied by upregulation of genes involved in acute inflammation ( AREG , EREG , CXCL8 , CCL4 , EGR3 , CLEC4E , CLEC6A ) and innate immunity ( TLR4 , EGR3) . Amphiregulin ( AREG ) and epiregulin ( EREG ) are type II cytokines linked to a wide variety of inflammatory conditions, such as rheumatoid arthritis, chronic airway disease and glomerulonephritis ( Yamane et al, 2008 ; Melderis et al, 2020 ). AREG skews monocytes and macrophages into a proinflammatory M1 phenotype, and the expression of EREG is induced by intermittent hypoxia ( Kyotani et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Acute Effects on the Human Peripheral Blood Transcriptome of Decompression Sickness Secondary to Scuba Diving

et al. 2021

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Decompression sickness (DCS) develops due to inert gas bubble formation in bodily tissues and in the circulation, leading to a wide range of potentially serious clinical manifestations. Its pathophysiology remains incompletely understood. In this study, we aim to explore changes in the human leukocyte transcriptome in divers with DCS compared to closely matched unaffected controls after uneventful diving. Cases (n = 7) were divers developing the typical cutis marmorata rash after diving with a confirmed clinical diagnosis of DCS. Controls (n = 6) were healthy divers who surfaced from a ≥25 msw dive without decompression violation or evidence of DCS. Blood was sampled at two separate time points—within 8 h of dive completion and 40–44 h later. Transcriptome analysis by RNA-Sequencing followed by bioinformatic analysis was carried out to identify differentially expressed genes and relate their function to biological pathways. In DCS cases, we identified enrichment of transcripts involved in acute inflammation, activation of innate immunity and free radical scavenging pathways, with specific upregulation of transcripts related to neutrophil function and degranulation. DCS-induced transcriptomic events were reversed at the second time point following exposure to hyperbaric oxygen. The observed changes are consistent with findings from animal models of DCS and highlight a continuum between the responses elicited by uneventful diving and diving complicated by DCS. This study sheds light on the inflammatory pathophysiology of DCS and the associated immune response. Such data may potentially be valuable in the search for novel treatments targeting this disease.

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Amphiregulin Aggravates Glomerulonephritis via Recruitment and Activation of Myeloid Cells

Cited by 14 publications

References 56 publications

Kidney GATA3+ regulatory T cells play roles in the convalescence stage after antibody-mediated renal injury

Kidney GATA3+ regulatory T cells play roles in the convalescence stage after antibody-mediated renal injury

Single-Cell RNA Sequencing Revealed CD14+ Monocytes Increased in Patients With Takayasu’s Arteritis Requiring Surgical Management

Acute Effects on the Human Peripheral Blood Transcriptome of Decompression Sickness Secondary to Scuba Diving

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