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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2021

01-12-2021 | Atopic Dermatitis | Research

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

Authors: Hui-Na Wang, Kunmei Ji, Li-Na Zhang, Chu-Chu Xie, Wei-Yong Li, Zhen-Fu Zhao, Jia-Jie Chen

Published in: Journal of Translational Medicine | Issue 1/2021

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Abstract

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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Literature
1.
2.
Kim DK, Kim HS, Kim AR, Kim JH, Kim B, Noh G, Kim HS, Beaven MA, Kim YM, Choi WS. DJ-1 regulates mast cell activation and IgE-mediated allergic responses. J Allergy Clin Immunol. 2013;131:1653–62.PubMedCrossRef
3.
4.
5.
6.
Kuehn HS, Swindle EJ, Kim MS, Beaven MA, Metcalfe DD, Gilfillan AM. The phosphoinositide 3-kinase-dependent activation of Btk is required for optimal eicosanoid production and generation of reactive oxygen species in antigen-stimulated mast cells. J Immunol. 2008;181:7706–12.PubMedCrossRef
7.
Kanagaratham C, El Ansari YS, Sallis BF, Hollister BA, Lewis OL, Minnicozzi SC, Oyoshi MK, Rosen R, Nurko S, Fiebiger E, Oettgen HC. Omeprazole inhibits IgE-mediated mast cell activation and allergic inflammation induced by ingested allergen in mice. J Allergy Clin Immunol. 2020;146:884.e885-893.e885.CrossRef
8.
Siraganian RP. Mast cell signal transduction from the high-affinity IgE receptor. Curr Opin Immunol. 2003;15:639–46.PubMedCrossRef
9.
Tsang F, Fred Wong WS. Inhibitors of tyrosine kinase signaling cascade attenuated antigen challenge of guinea-pig airways in vitro. Am J Respir Crit Care Med. 2000;162:126–33.PubMedCrossRef
10.
Rivera J, Gilfillan AM. Molecular regulation of mast cell activation. J Allergy Clin Immunol. 2006;117:1214–25 (quiz 1226).PubMedCrossRef
11.
Jin F, Li X, Deng Y, Timilshina M, Huang B, Kim DY, Chang JH, Ichinose H, Baek SH, Murakami M, et al. The orphan nuclear receptor NR4A1 promotes FcepsilonRI-stimulated mast cell activation and anaphylaxis by counteracting the inhibitory LKB1/AMPK axis. Allergy. 2019;74:1145–56.PubMedCrossRef
12.
Yang YJ, Chen W, Edgar A, Li B, Molkentin JD, Berman JN, Lin TJ. Rcan1 negatively regulates Fc epsilonRI-mediated signaling and mast cell function. J Exp Med. 2009;206:195–207.PubMedPubMedCentralCrossRef
13.
Lee YN, Tuckerman J, Nechushtan H, Schutz G, Razin E, Angel P. c-Fos as a regulator of degranulation and cytokine production in FcepsilonRI-activated mast cells. J Immunol. 2004;173:2571–7.PubMedCrossRef
14.
Wagner EF. Bone development and inflammatory disease is regulated by AP-1 (Fos/Jun). Ann Rheum Dis. 2010;69(Suppl 1):i86-88.PubMedCrossRef
15.
Baranes D, Razin E. Protein kinase C regulates proliferation of mast cells and the expression of the mRNAs of fos and jun proto-oncogenes during activation by IgE-Ag or calcium ionophore A23187. Blood. 1991;78:2354–64.PubMedCrossRef
16.
Koga K, Takaesu G, Yoshida R, Nakaya M, Kobayashi T, Kinjyo I, Yoshimura A. Cyclic adenosine monophosphate suppresses the transcription of proinflammatory cytokines via the phosphorylated c-Fos protein. Immunity. 2009;30:372–83.PubMedCrossRef
17.
18.
MacNeil AJ, Junkins RD, Wu Z, Lin TJ. Stem cell factor induces AP-1-dependent mast cell IL-6 production via MAPK kinase 3 activity. J Leukoc Biol. 2014;95:903–15.PubMedCrossRef
19.
Weng Z, Patel AB, Panagiotidou S, Theoharides TC. The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells. J Allergy Clin Immunol. 2015;135:1044–52.PubMedCrossRef
20.
Ochi H, De Jesus NH, Hsieh FH, Austen KF, Boyce JA. IL-4 and -5 prime human mast cells for different profiles of IgE-dependent cytokine production. Proc Natl Acad Sci USA. 2000;97:10509–13.PubMedCrossRefPubMedCentral
21.
MacNeil AJ, Yang YJ, Lin TJ. MAPK kinase 3 specifically regulates Fc epsilonRI-mediated IL-4 production by mast cells. J Immunol. 2011;187:3374–82.PubMedCrossRef
22.
23.
Kim YY, Hur G, Lee SW, Lee SJ, Lee S, Kim SH, Rho MC. AGK2 ameliorates mast cell-mediated allergic airway inflammation and fibrosis by inhibiting FcepsilonRI/TGF-beta signaling pathway. Pharmacol Res. 2020;159:105027.PubMedCrossRef
24.
Natarajan KN, Miao Z, Jiang M, Huang X, Zhou H, Xie J, Wang C, Qin S, Zhao Z, Wu L, et al. Comparative analysis of sequencing technologies for single-cell transcriptomics. Genome Biol. 2019;20:70.PubMedPubMedCentralCrossRef
25.
Li R, Li Y, Kristiansen K, Wang J. SOAP: short oligonucleotide alignment program. Bioinformatics. 2008;24:713–4.PubMedCrossRef
26.
27.
Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinform. 2011;12:323.CrossRef
28.
29.
Lee JH, Kim JW, Ko NY, Mun SH, Her E, Kim BK, Han JW, Lee HY, Beaven MA, Kim YM, Choi WS. Curcumin, a constituent of curry, suppresses IgE-mediated allergic response and mast cell activation at the level of Syk. J Allergy Clin Immunol. 2008;121:1225–31.PubMedCrossRef
30.
Fu Y, Wang J, Panangipalli G, Ulrich BJ, Koh B, Xu C, Kharwadkar R, Chu X, Wang Y, Gao H, et al. STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus. Nat Commun. 2020;11:4882.PubMedPubMedCentralCrossRef
31.
Wechsler JB, Hsu CL, Bryce PJ. IgE-mediated mast cell responses are inhibited by thymol-mediated, activation-induced cell death in skin inflammation. J Allergy Clin Immunol. 2014;133:1735–43.PubMedPubMedCentralCrossRef
32.
Kim YY, Je IG, Kim MJ, Kang BC, Choi YA, Baek MC, Lee B, Choi JK, Park HR, Shin TY, et al. 2-Hydroxy-3-methoxybenzoic acid attenuates mast cell-mediated allergic reaction in mice via modulation of the FcepsilonRI signaling pathway. Acta Pharmacol Sin. 2017;38:90–9.PubMedCrossRef
33.
Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic dermatitis. Nat Rev Dis Prim. 2018;4:1.PubMedCrossRef
34.
Fujita T, Fujimoto M, Matsushita T, Shimada Y, Hasegawa M, Kuwano Y, Ogawa F, Takehara K, Sato S. Phase-dependent roles of E-selectin during chronic contact hypersensitivity responses. Am J Pathol. 2007;170:1649–58.PubMedPubMedCentralCrossRef
35.
Joseph LB, Composto GM, Perez RM, Kim HD, Casillas RP, Heindel ND, Young SC, Lacey CJ, Saxena J, Guillon CD, et al. Sulfur mustard induced mast cell degranulation in mouse skin is inhibited by a novel anti-inflammatory and anticholinergic bifunctional prodrug. Toxicol Lett. 2018;293:77–81.PubMedCrossRef
36.
Gonzalez-de-Olano D, Alvarez-Twose I. Mast cells as key players in allergy and inflammation. J Investig Allergol Clin Immunol. 2018;28:365–78.PubMedCrossRef
37.
Gangwar RS, Landolina N, Arpinati L, Levi-Schaffer F. Mast cell and eosinophil surface receptors as targets for anti-allergic therapy. Pharmacol Ther. 2017;170:37–63.PubMedCrossRef
38.
Li B, Berman J, Tang JT, Lin TJ. The early growth response factor-1 is involved in stem cell factor (SCF)-induced interleukin 13 production by mast cells, but is dispensable for SCF-dependent mast cell growth. J Biol Chem. 2007;282:22573–81.PubMedCrossRef
39.
Li B, Power MR, Lin TJ. De novo synthesis of early growth response factor-1 is required for the full responsiveness of mast cells to produce TNF and IL-13 by IgE and antigen stimulation. Blood. 2006;107:2814–20.PubMedCrossRef
40.
Bischoff SC, Sellge G, Lorentz A, Sebald W, Raab R, Manns MP. IL-4 enhances proliferation and mediator release in mature human mast cells. Proc Natl Acad Sci USA. 1999;96:8080–5.PubMedCrossRefPubMedCentral
41.
42.
Wynn TA. Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol. 2015;15:271–82.PubMedCrossRef
43.
Desmet C, Gosset P, Henry E, Garze V, Faisca P, Vos N, Jaspar F, Melotte D, Lambrecht B, Desmecht D, et al. Treatment of experimental asthma by decoy-mediated local inhibition of activator protein-1. Am J Respir Crit Care Med. 2005;172:671–8.PubMedCrossRef
44.
Nguyen C, Teo JL, Matsuda A, Eguchi M, Chi EY, Henderson WR Jr, Kahn M. Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma. Proc Natl Acad Sci USA. 2003;100:1169–73.PubMedCrossRefPubMedCentral
45.
Angel P, Szabowski A. Function of AP-1 target genes in mesenchymal–epithelial cross-talk in skin. Biochem Pharmacol. 2002;64:949–56.PubMedCrossRef
46.
Li Y, Gao J, Kamran M, Harmacek L, Danhorn T, Leach SM, O’Connor BP, Hagman JR, Huang H. GATA2 regulates mast cell identity and responsiveness to antigenic stimulation by promoting chromatin remodeling at super-enhancers. Nat Commun. 2021;12:494.PubMedPubMedCentralCrossRef
47.
Aikawa Y, Morimoto K, Yamamoto T, Chaki H, Hashiramoto A, Narita H, Hirono S, Shiozawa S. Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1. Nat Biotechnol. 2008;26:817–23.PubMedCrossRef
48.
Ishida M, Ueki M, Morishita J, Ueno M, Shiozawa S, Maekawa N. T-5224, a selective inhibitor of c-Fos/activator protein-1, improves survival by inhibiting serum high mobility group box-1 in lethal lipopolysaccharide-induced acute kidney injury model. J Intensive Care. 2015;3:49.PubMedPubMedCentralCrossRef
49.
Izuta S, Ueki M, Ueno M, Nishina K, Shiozawa S, Maekawa N. T-5224, a selective inhibitor of c-Fos/activator protein-1, attenuates lipopolysaccharide-induced liver injury in mice. Biotechnol Lett. 2012;34:2175–82.PubMedCrossRef
50.
Makino H, Seki S, Yahara Y, Shiozawa S, Aikawa Y, Motomura H, Nogami M, Watanabe K, Sainoh T, Ito H, et al. A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain. Sci Rep. 2017;7:16983.PubMedPubMedCentralCrossRef
51.
Tanaka S, Ishii T, Sato F, Toi M, Itou J. Eribulin mesylate-induced c-Fos upregulation enhances cell survival in breast cancer cell lines. Biochem Biophys Res Commun. 2020;526:154–7.PubMedCrossRef
52.
Zhang LN, Ji K, Sun YT, Hou YB, Chen JJ. Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo. Br J Pharmacol. 2020;177:2848–59.PubMedPubMedCentralCrossRef
53.
Fu S, Ni S, Wang D, Fu M, Hong T. Berberine suppresses mast cell-mediated allergic responses via regulating FcɛRI-mediated and MAPK signaling. Int Immunopharmacol. 2019;71:1–6.PubMedCrossRef
54.
55.
Uchihashi S, Fukumoto H, Onoda M, Hayakawa H, Ikushiro S, Sakaki T. Metabolism of the c-Fos/activator protein-1 inhibitor T-5224 by multiple human UDP-glucuronosyltransferase isoforms. Drug Metab Dispos. 2011;39:803–13.PubMedCrossRef
56.
57.
Nakamura Y, Oscherwitz J, Cease KB, Chan SM, Muñoz-Planillo R, Hasegawa M, Villaruz AE, Cheung GY, McGavin MJ, Travers JB, et al. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature. 2013;503:397–401.PubMedPubMedCentralCrossRef
Metadata
Title
Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis
Authors
Hui-Na Wang
Kunmei Ji
Li-Na Zhang
Chu-Chu Xie
Wei-Yong Li
Zhen-Fu Zhao
Jia-Jie Chen
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2021
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-021-02932-0

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