Guidance of super-enhancers in regulation of IL-9 induction and airway inflammation

Xiao, Xiang; Fan, Yihui; Li, Junhui; Zhang, Xiaolong; Lou, Xudong; Yu, Dou; Shi, Xinling; Lan, Peixiang; Xiao, Yue; Minze, Laurie J.; Li, Xian Chang

doi:10.1084/jem.20170928

Cited by 55 publications

(51 citation statements)

References 38 publications

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“…In allergic lung inflammation, Xiao et al (19) found that the acetylation of histones (specifically, H3K27) mediates IL-9 expression. Lloyd and Harker (18) also reported that acetylation of histones mediates IL-9 in asthma, and inhibition of H3K27 acetylation decreases the expression of IL-9.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Histone H3K27 Acetylation Orchestrates Interleukin-9-Mediated and Plays an Anti-Inflammatory Role in Cisplatin-Induced Acute Kidney Injury

et al. 2020

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Nephrotoxicity is a major side effect of cisplatin (CP)-and platinum-related chemotherapy, and inflammation contributes to disease pathogenesis. Interleukin-9 (IL-9) is a pleiotropic cytokine associated with inflammation. Here, we investigated the key role of IL-9 as a regulator of protective mechanisms in CP-induced acute kidney injury (AKI). We observed that IL-9 was decreased not only in a CP-induced AKI mouse model but also in THP-1 and RAW264.7 cell lines. Seventy-two hours post-CP injection, renal dysfunction and tubule injury were significantly attenuated in IL-9 overexpression adeno-associated virus 9 (AAV9)-treated mice. The levels of serum urea, serum creatinine, kidney injury molecule-1 (KIM-1), and histological damage were partially diminished following treatment with IL-9. The renoprotective effects of IL-9 may be attributed to the regulation of cytokines, and we found that IL-9 acted on macrophages in a regulatory manner, promoting an anti-inflammatory phenotype. Furthermore, IL-9 enhanced the suppression of macrophage-driven renal inflammation. Inhibition of H3K27 acetylation orchestrated IL-9-mediated renoprotection in CP-induced AKI. Thus, our findings indicate novel and potent anti-inflammatory properties of IL-9 that confer preservation of kidney function and structure in CP-induced AKI, which may counteract kidney disease procession.

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Section: Discussionmentioning

confidence: 99%

“…Inhibition of H3K27 acetylation could decrease the expression of IL-9. Xiao et al (19) also found that acetylation of histones (specifically, H3K27) promoted transcription of IL-9. H3K27 is a specific histone protein (H3) that is acetylated at lysine 27 (H3K27Ac), a marker of transcriptional activity.…”

Section: Introductionmentioning

confidence: 96%

Inhibition of Histone H3K27 Acetylation Orchestrates Interleukin-9-Mediated and Plays an Anti-Inflammatory Role in Cisplatin-Induced Acute Kidney Injury

et al. 2020

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“…Unlike other costimulatory molecules, OX40 is not expressed by resting naive T cells, but its expression is rapidly induced upon T cell activation, and OX40 costimulation plays a critical role in cell survival, proliferation, and generation of memory cells (Croft, 2010). We and others have shown that OX40 regulates the induction of multiple T helper (T H ) cell subsets, primarily through triggering chromatin modifications that control accessibility of key transcription factors to target loci (Xiao et al, 2016, 2018). In certain models, OX40 strongly promotes the induction of T H 1, T H 2, and T H 9 cells, whereas in other conditions, it inhibits the generation of T H 17 cells and Foxp3 + Tregs (Ito et al, 2005; Li et al, 2008; Vu et al, 2007; Xiao et al, 2012a).…”

Section: Introductionmentioning

confidence: 99%

OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms

et al. 2018

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SUMMARY Naive CD4+ T cells can be converted to Foxp3+ T regulatory cells (Tregs) in the periphery (iTregs), where induction of Foxp3 gene expression is central to Treg differentiation. OX40 signaling is known to inhibit Foxp3 expression and Treg induction, but the underlying mechanisms remain poorly defined. Here, we found that OX40 costimulation activates two distinct molecular pathways to suppress Foxp3 expression in freshly activated naive CD4+ T cells. Specifically, OX40 upregulates BATF3 and BATF, which produce a closed chromatin configuration to repress Foxp3 expression in a Sirt1/7-dependent manner. Moreover, OX40 can also activate the AKT-mTOR pathway, especially in the absence of BATF3 and BATF, to inhibit Foxp3 induction, and this is mediated by phos-phorylation and nuclear exclusion of the transcription factor Foxo1. Taken together, our results provide key mechanistic insights into how OX40 inhibits Foxp3 expression and Treg induction in the periphery.

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“…In a different model, we showed that RelB is capable of recruiting the histone acetyltransferase p300/CBP to the Il9 locus to catalyze H3K27 acetylation (an active chromatin mark), consequently mediating robust Th9 induction. 59 However, the factors determining the selectivity of RelB in engaging functionally different chromatin modifiers, separate from its classic role as a transcription factor, remain unknown and warrant further investigation.…”

Section: Nf-κb Family Members As Chromatin Modifiersmentioning

confidence: 99%

“…In a mouse model of allergic lung inflammation, we showed that the challenge of ovalbumin-sensitized mice induces extensive airway inflammation, especially when the OX40 receptor is concurrently stimulated. 59 Further in vitro studies showed that OX40 signaling is exceptionally potent in driving the differentiation of Th9 cells, which are responsible for epithelial hyperplasia, mucin production, and mast cell accumulation in the airways. Interestingly, the induction of Th9 cells by OX40 receptor stimulation is mediated primarily by the formation of superenhancers at the Il9 locus.…”

Section: Chromatin Modifier-targeted Interventions As Potential Theramentioning

confidence: 99%

Transcriptional and epigenetic regulation of immune tolerance: roles of the NF-κB family members

et al. 2019

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Immune tolerance is a highly regulated state and involves diverse mechanisms. Central to the induction of tolerance is the targeted modulation of T-cell activities (both effector and regulatory), in which transcription factors play a significant role. The nuclear factor kappa-B (NF-κB) family is a family of transcription factors that not only are critically involved in diverse T-cell responses but also are regulated by many mechanisms to maintain tolerance and T-cell homeostasis. NF-κB, as a transcription factor, has been extensively studied in recent decades, and the molecular mechanisms that regulate NF-κB activities have been well documented. However, recent studies have revealed exciting new roles for NF-κB; in addition to its transcriptional activity, NF-κB can also activate diverse epigenetic mechanisms that mediate extensive chromatin remodeling of target genes to regulate T-cell activities. In this review article, we highlight recent discoveries and emerging opportunities in targeting NF-κB family members as well as their associated chromatin modifiers in the induction of immune tolerance and in the clinical treatment of immune diseases.

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Guidance of super-enhancers in regulation of IL-9 induction and airway inflammation

Abstract: Xiao et al. demonstrate that formation of super-enhancers at Il9 locus is critical for robust IL-9 expression and Th9 cell induction, and assembly of Il9 super-enhancers is driven by OX40-mediated chromatin acetylation.

Cited by 55 publications

References 38 publications

Inhibition of Histone H3K27 Acetylation Orchestrates Interleukin-9-Mediated and Plays an Anti-Inflammatory Role in Cisplatin-Induced Acute Kidney Injury

Inhibition of Histone H3K27 Acetylation Orchestrates Interleukin-9-Mediated and Plays an Anti-Inflammatory Role in Cisplatin-Induced Acute Kidney Injury

OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms

Transcriptional and epigenetic regulation of immune tolerance: roles of the NF-κB family members

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