STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus

Fu, Yukui; Wang, Jocelyn; Panangipalli, Gayathri; Ulrich, Bernd; Koh, Byunghee; Xu, Chengxian; Kharwadkar, Rakshin; Chu, Xun; Wang, Yue; Gao, Hongyu; Wu, Wenting; Sun, Jie; Tepper, Robert S.; Zhou, Baohua; Janga, Sarath Chandra; Yang, Kai; Kaplan, Mark H.

doi:10.1038/s41467-020-18648-6

Cited by 35 publications

(23 citation statements)

References 69 publications

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“…RBLs were collected as previously described [ 30 ]. Proteins were crosslinked to DNA by adding 270 µL of 37% formaldehyde to 10 mL culture medium (final concentration, 1%).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

Wang

Zhang

et al. 2021

J Transl Med

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Background Activator protein-1 (AP1), a c-Fos–JUN transcription factor complex, mediates many cytobiological processes. c-Fos has been implicated in immunoglobulin (Ig)E activation of mast cells (MCs) via high-affinity IgE Fc receptor (FcεRI) binding. This study examined c-Fos involvement in MC activation and tested the effects of the c-Fos/AP1 inhibitor T-5224 on MCs activation and allergic responses. Methods In vitro studies were conducted with two MC model systems: rat basophilic leukemia cells (RBLs) and mouse bone marrow derived mast cells (BMMCs). MC degranulation and effector functions were examined with β-hexosaminidase release and cytokine secretion assays. c-Fos/AP1 was inhibited with T-5224. c-Fos activity was suppressed with short hairpin RNA targeting c-Fos (shFos). In vivo immune responses were evaluated in passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models, as well as in an oxazolone (OXA)-induced model of atopic dermatitis, a common allergic disease. Results c-Fos expression was elevated transcriptionally and translationally in IgE-stimulated MCs. c-Fos binding of the Egr1 (early growth response 1) promoter upregulated Egr1 transcription, leading to production of interleukin (IL)4. T-5224 reduced FcεRI-mediated MC degranulation (evidenced by β-hexosaminidase activity and histamine levels) and diminished EGR1 and IL4 expression. T-5224 attenuated IgE-mediated allergic responses in PCA and ASA models, and it suppressed MC-mediated atopic dermatitis in mice. Conclusion IgE binding can activate MCs via a c-Fos/Egr1/IL-4 axis. T-5224 suppresses MC activation in vitro and in vivo and thus represents a promising potential strategy for targeting MC activation to treat allergic diseases.

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“…RBLs were collected as previously described [ 30 ]. Proteins were crosslinked to DNA by adding 270 µL of 37% formaldehyde to 10 mL culture medium (final concentration, 1%).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

Wang

Zhang

et al. 2021

J Transl Med

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“…The recent demonstration of potent anti-tumor activity from T helper 9 (Th9) and other IL-9-producing cells supported these cells as an attractive strategy for cancer cell therapy 1 , 2 . Adoptive transfer of Th9 cells or other IL-9-producing cells limits tumor growth, particularly in models of melanoma 3 – 7 . IL-9 mediates anti-tumor effects through multiple mechanisms including impacting the function of T cells, mast cells and dendritic cells (DCs), and by directly killing tumor cells 5 , 6 , 8 , 9 .…”

Section: Introductionmentioning

confidence: 99%

Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9

Pajulas

Wang

et al. 2022

Nat Commun

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Although IL-9 has potent anti-tumor activity in adoptive cell transfer therapy, some models suggest that it can promote tumor growth. Here, we show that IL-9 signaling is associated with poor outcomes in patients with various forms of lung cancer, and is required for lung tumor growth in multiple mouse models. CD4+ T cell-derived IL-9 promotes the expansion of both CD11c+ and CD11c− interstitial macrophage populations in lung tumor models. Mechanistically, the IL-9/macrophage axis requires arginase 1 (Arg1) to mediate tumor growth. Indeed, adoptive transfer of Arg1+ but not Arg1- lung macrophages to Il9r−/− mice promotes tumor growth. Moreover, targeting IL-9 signaling using macrophage-specific nanoparticles restricts lung tumor growth in mice. Lastly, elevated expression of IL-9R and Arg1 in tumor lesions is associated with poor prognosis in lung cancer patients. Thus, our study suggests the IL-9/macrophage/Arg1 axis is a potential therapeutic target for lung cancer therapy.

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“…STAT5 is a well-described early remodeling factor invoked by IL-2 family cytokines which establishes enhancer landscapes within T-cell lineages 24 . It has a known role in recruiting chromatin remodelers in Treg cells 25 and promotes accessibility at the IL-9 locus in Th17 cells 26 . NFκB induction occurs in response to TCR signaling following intracellular calcium mobilization and is needed for the induction of inflammatory responses 27 .…”

Section: Discussionmentioning

confidence: 99%

Mapping the landscape of chromatin dynamics during naïve CD4+ T-cell activation

Iqbal

Serralha

Kaur

et al. 2021

Sci Rep

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T-cell activation induces context-specific gene expression programs that promote energy generation and biosynthesis, progression through the cell cycle and ultimately cell differentiation. The aim of this study was to apply the omni ATAC-seq method to characterize the landscape of chromatin changes induced by T-cell activation in mature naïve CD4+ T-cells. Using a well-established ex vivo protocol of canonical T-cell receptor signaling, we generated genome-wide chromatin maps of naïve T-cells from pediatric donors in quiescent or recently activated states. We identified thousands of individual chromatin accessibility peaks that are associated with T-cell activation, the majority of which were annotated intronic and intergenic enhancer regions. A core set of 3268 gene promoters underwent chromatin remodeling and concomitant changes in gene expression in response to activation, and were enriched in multiple pathways controlling cell cycle regulation, metabolism, inflammatory response genes and cell survival. Leukemia inhibitory factor (LIF) was among those factors that gained the highest accessibility and expression, in addition to IL2-STAT5 dependent chromatin remodeling in the T-cell activation response. Using publicly available data we found the chromatin response was far more dynamic at 24-h compared with 72-h post-activation. In total 546 associations were reproduced at both time-points with similar strength of evidence and directionality of effect. At the pathways level, the IL2-STAT5, KRAS signalling and UV response pathways were replicable at both time-points, although differentially modulated from 24 to 72 h post-activation.

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STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus

Cited by 35 publications

References 69 publications

Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9

Mapping the landscape of chromatin dynamics during naïve CD4+ T-cell activation

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