The transcription factor Bhlhe40 is a switch of inflammatory versus antiinflammatory Th1 cell fate determination

Yu, Fang; Sharma, Suveena; Janković, Dragana; Gurram, Rama Krishna; Su, Pan; Hu, Gangqing; Li, Rao; Rieder, Sadiye Amcaoglu; Zhao, Keji; Sun, Bing; Zhu, Jinfang

doi:10.1084/jem.20170155

Cited by 109 publications

(141 citation statements)

References 33 publications

(45 reference statements)

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“…28 In autoimmune neuroinflammation, BHLHE40 in Th cells contributes to disease progression. 32 To date, the potential roles of BHLHE40 in H pylori infection and H pylori-induced gastritis remain unknown. 32 To date, the potential roles of BHLHE40 in H pylori infection and H pylori-induced gastritis remain unknown.…”

Section: Discussionmentioning

confidence: 99%

Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p‐STAT3 in Helicobacter pylori ‐associated gastritis

Teng

Zhao

et al. 2019

FASEB j.

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BHLHE40, a member of the basic helix-loop-helix transcription factor family, has been reported to play an important role in inflammatory diseases. However, the regulation and function of BHLHE40 in Helicobacter pylori (H pylori)-associated gastritis is unknown. We observed that gastric BHLHE40 was significantly elevated in patients and mice with H pylori infection. Then, we demonstrate that H pyloriinfected GECs express BHLHE40 via cagA-ERK pathway. BHLHE40 translocates to cell nucleus, and then binds to cagA protein-activated p-STAT3 (Tyr705). The complex increases chemotactic factor CXCL12 expression (production). Release of CXCL12 from GECs fosters CD4 + T cell infiltration in the gastric mucosa. Our results identify the cagA-BHLHE40-CXCL12 axis that contributes to inflammatory response in gastric mucosa during H pylori infection.

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Section: Discussionmentioning

confidence: 99%

Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p‐STAT3 in Helicobacter pylori ‐associated gastritis

Teng

Zhao

et al. 2019

FASEB j.

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“…Interestingly, BHLH40 expression has been observed in a wide range of cells and tissues including T-cells, macrophages, dendritic cells and the gastric epithelium (Lin et al, 2014;Teng et al, 2020). BHLH40 was found to control cytokine production by T-cells thereby playing a critical role in the development of autoimmune neuroinflammation (Lin et al, 2014;Yu et al, 2018). Finally, our analyses confirm previous reports of Forkhead BoxM1 (FOXM1, also HFH-11) transcription factor being expressed in embryonic epithelial cell with its expressing becoming reactivated in adult cell types by proliferative signals or oxidative stress (Ye et al, 1997).…”

Section: Linking Fetal Gut Epithelial Development To Childhood-onset CDmentioning

confidence: 99%

Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease

Elmentaite

Ross

James

et al. 2020

Preprint

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Human gut development requires the orchestrated interaction of various differentiating cell types. Here we generate an in-depth single-cell map of the developing human intestine at 6-10 weeks post-conception, a period marked by crypt-villus formation. Our analysis reveals the transcriptional profile of cycling epithelial precursor cells, which are distinct from LGR5expressing cells. We use computational analyses to show that these cells contribute to differentiated cell subsets directly and indirectly via the generation of LGR5-expressing stem cells and receive signals from the surrounding mesenchymal cells. Furthermore, we draw parallels between the transcriptomes of ex vivo tissues and in vitro fetal organoids, revealing the maturation of organoid cultures in a dish. Lastly, we compare scRNAseq profiles from paediatric Crohn's disease epithelium alongside matched healthy controls to reveal disease associated changes in epithelial composition. Contrasting these with the fetal profiles reveals re-activation of fetal transcription factors in Crohn's disease epithelium. Our study provides a unique resource, available at www.gutcellatlas.org, and underscores the importance of unravelling fetal development in understanding disease.

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“…Although expression of the transcription factor cMaf is not overtly high in aTregs (2), it is increased over that of conventional Tregs and might represent another transcription factor that could regulate IL-10 production by aTregs (30). In T cells, IL-10 expression can be repressed by the transcription factor bHLHe40 (31,32). bHLHe40 is highly expressed in aTregs under standard diet conditions (2), indicating that an elaborate interplay between multiple transcription factors likely occurs in aTregs, enabling them to produce IL-10 in the VAT (20).…”

Section: Discussionmentioning

confidence: 99%

Blimp-1 in adipose resident Tregs controls adipocyte beiging and obesity

et al. 2019

Preprint

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Here we show that ablation of Blimp-1 in adipose tissue resident Tregs (aTregs) leads to decreased IL-10 production, resulting in increased Ucp-1 expression and beiging by adipocytes and protection from diet-induced obesity and insulin resistance. ABSTRACTCrosstalk between the immune system and adipocytes is critical for maintaining tissue homeostasis and regulating chronic systemic inflammation during diet-induced obesity (DIO). How visceral adipose tissue resident regulatory T cells (aTregs) signal to adipocytes in the visceral adipose tissue (VAT) is not understood. Here we show that Treg-specific ablation of the transcriptional regulator Blimp-1 resulted in increased insulin sensitivity, decreased body weight and increased Ucp-1 in adipocytes in high fat diet (HFD)-fed mice. Mechanistically, we demonstrate that Blimp-1 drives IL-10 production in Tregs, thus suppressing beiging and energy expenditure in adipocytes.Moreover, IL-10 mRNA expression positively correlated with increasing body weight in humans.These findings reveal a surprising relationship between aTregs and adipocytes in promoting insulin resistance during excessive caloric intake, placing Blimp-1-regulated IL-10 expression by aTregs at a critical juncture in the development of obesity and its associated comorbidities in mice and humans.We would like to acknowledge Drs. McGeachy and Kane for critical reading the manuscript and all members of the D'Cruz lab for their constructive criticism and comments. We would also like to thank the University of Pittsburgh Unified Flow Core for assistance with cell sorting and flow cytometry. The authors declare no competing interests.

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The transcription factor Bhlhe40 is a switch of inflammatory versus antiinflammatory Th1 cell fate determination

Cited by 109 publications

References 33 publications

Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p‐STAT3 in Helicobacter pylori ‐associated gastritis

Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p‐STAT3 in Helicobacter pylori ‐associated gastritis

Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease

Blimp-1 in adipose resident Tregs controls adipocyte beiging and obesity

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