CCAAT/Enhancer-binding Protein β Promotes Pathogenesis of EAE

Overview

Journal Cytokine

Specialties Allergy & Immunology
Biology

Date 2017 Jan 16

PMID 28088614

Citations 21

Authors

Michelle R Simpson-Abelson

Gerard Hernandez-Mir

Erin E Childs

J Agustin Cruz

Amanda C Poholek

Ansuman Chattopadhyay

Sarah L Gaffen

Mandy J McGeachy

Affiliations

Soon will be listed here.

Abstract

The CCAAT/Enhancer Binding Protein β (C/EBPβ) transcription factor is activated by multiple inflammatory stimuli, including IL-17 and LPS, and C/EBPβ itself regulates numerous genes involved in inflammation. However, the role of C/EBPβ in driving autoimmunity is not well understood. Here, we demonstrate that Cebpb mice are resistant to EAE. Cebpb mice exhibited reduced lymphocyte and APC infiltration into CNS following EAE induction. Furthermore, MOG-induced Th17 cytokine production was impaired in draining LN, indicating defects in Th17 cell priming. In vitro Th17 polarization studies indicated that T cell responses are not inherently defective, instead supporting the known roles for C/EBPβ in myeloid lineage cell activation as the likely mechanism for defective Th17 priming in vivo. However, we did uncover an unexpected role for C/EBPβ in regulating ll23r expression in APCs. ChIP assays confirmed that C/EBPβ binds directly to the Il23r gene promoter in dendritic cells and Th17 cells. These data establish C/EBPβ as a key driver of autoimmune inflammation in EAE, and propose a novel role for C/EBPβ in regulation of IL-23R expression.

Citing Articles

C/EBPβ transcription factor promotes alcohol-induced liver fibrosis in males via HDL remodeling.

Schonfeld M, Nataraj K, Weinman S, Tikhanovich I Hepatol Commun. 2025; 9(3).

PMID: 39969482 PMC: 11841851. DOI: 10.1097/HC9.0000000000000645.

Alghamdi K, Kassar R, Farrash W, Obaid A, Idris S, Siddig A Int J Mol Sci. 2024; 25(17).

PMID: 39273699 PMC: 11396460. DOI: 10.3390/ijms25179751.

Transcriptome Study of 2 Black Cohorts Reveals Long Noncoding RNAs Associated With Hypertension-Related mRNAs.

Abbas M, Goodney G, Vargas J, Gaye A J Am Heart Assoc. 2024; 13(11):e034417.

PMID: 38818927 PMC: 11255619. DOI: 10.1161/JAHA.124.034417.

IκBζ is an essential mediator of immunity to oropharyngeal candidiasis.

Taylor T, Coleman B, Arunkumar S, Dey I, Dillon J, Ponde N Cell Host Microbe. 2023; 31(10):1700-1713.e4.

PMID: 37725983 PMC: 10591851. DOI: 10.1016/j.chom.2023.08.016.

Soluble adenylyl cyclase contributes to imiquimod-mediated inflammation and is a potential therapeutic target in psoriasis.

You J, Reilly M, Eljalby M, Bareja R, Yusupova M, Vyas N Exp Dermatol. 2023; 32(7):1051-1062.

PMID: 37039485 PMC: 10523866. DOI: 10.1111/exd.14811.

References

Sturner K, Borgmeyer U, Schulze C, Pless O, Martin R . A multiple sclerosis-associated variant of CBLB links genetic risk with type I IFN function. J Immunol. 2014; 193(9):4439-47. DOI: 10.4049/jimmunol.1303077. View

McGeachy M, Bak-Jensen K, Chen Y, Tato C, Blumenschein W, Mcclanahan T . TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007; 8(12):1390-7. DOI: 10.1038/ni1539. View

Uematsu S, Kaisho T, Tanaka T, Matsumoto M, Yamakami M, Omori H . The C/EBP beta isoform 34-kDa LAP is responsible for NF-IL-6-mediated gene induction in activated macrophages, but is not essential for intracellular bacteria killing. J Immunol. 2007; 179(8):5378-86. DOI: 10.4049/jimmunol.179.8.5378. View

Baeten D, Sieper J, Braun J, Baraliakos X, Dougados M, Emery P . Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis. N Engl J Med. 2015; 373(26):2534-48. DOI: 10.1056/NEJMoa1505066. View

Duhen R, Glatigny S, Arbelaez C, Blair T, Oukka M, Bettelli E . Cutting edge: the pathogenicity of IFN-γ-producing Th17 cells is independent of T-bet. J Immunol. 2013; 190(9):4478-82. PMC: 3633668. DOI: 10.4049/jimmunol.1203172. View

Simpson-Abelson M, Childs E, Ferreira M, Bishu S, Conti H, Gaffen S . C/EBPβ Promotes Immunity to Oral Candidiasis through Regulation of β-Defensins. PLoS One. 2015; 10(8):e0136538. PMC: 4552893. DOI: 10.1371/journal.pone.0136538. View

Ahmed M, Gaffen S . IL-17 in obesity and adipogenesis. Cytokine Growth Factor Rev. 2010; 21(6):449-53. PMC: 3259710. DOI: 10.1016/j.cytogfr.2010.10.005. View

Patel D, King C, Bailey S, Holt J, Venkatachalam K, Agrawal A . Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-kappaB and C/EBPbeta activation. J Biol Chem. 2007; 282(37):27229-27238. PMC: 3818724. DOI: 10.1074/jbc.M703250200. View

Ruddy M, Shen F, Smith J, Sharma A, Gaffen S . Interleukin-17 regulates expression of the CXC chemokine LIX/CXCL5 in osteoblasts: implications for inflammation and neutrophil recruitment. J Leukoc Biol. 2004; 76(1):135-44. DOI: 10.1189/jlb.0204065. View

10.

Lee Y, Awasthi A, Yosef N, Quintana F, Xiao S, Peters A . Induction and molecular signature of pathogenic TH17 cells. Nat Immunol. 2012; 13(10):991-9. PMC: 3459594. DOI: 10.1038/ni.2416. View

11.

Yoon J, Leyva-Castillo J, Wang G, Galand C, Oyoshi M, Kumar L . IL-23 induced in keratinocytes by endogenous TLR4 ligands polarizes dendritic cells to drive IL-22 responses to skin immunization. J Exp Med. 2016; 213(10):2147-66. PMC: 5032726. DOI: 10.1084/jem.20150376. View

12.

Shen F, Li N, Gade P, Kalvakolanu D, Weibley T, Doble B . IL-17 receptor signaling inhibits C/EBPbeta by sequential phosphorylation of the regulatory 2 domain. Sci Signal. 2009; 2(59):ra8. PMC: 2754870. DOI: 10.1126/scisignal.2000066. View

13.

Ahmed M, Gaffen S . IL-17 inhibits adipogenesis in part via C/EBPα, PPARγ and Krüppel-like factors. Cytokine. 2013; 61(3):898-905. PMC: 3595389. DOI: 10.1016/j.cyto.2012.12.007. View

14.

Korn T, Bettelli E, Oukka M, Kuchroo V . IL-17 and Th17 Cells. Annu Rev Immunol. 2009; 27:485-517. DOI: 10.1146/annurev.immunol.021908.132710. View

15.

Maitra A, Shen F, Hanel W, Mossman K, Tocker J, Swart D . Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression. Proc Natl Acad Sci U S A. 2007; 104(18):7506-11. PMC: 1863505. DOI: 10.1073/pnas.0611589104. View

16.

Haines C, Chen Y, Blumenschein W, Jain R, Chang C, Joyce-Shaikh B . Autoimmune memory T helper 17 cell function and expansion are dependent on interleukin-23. Cell Rep. 2013; 3(5):1378-88. DOI: 10.1016/j.celrep.2013.03.035. View

17.

Ruddy M, Wong G, Liu X, Yamamoto H, Kasayama S, Kirkwood K . Functional cooperation between interleukin-17 and tumor necrosis factor-alpha is mediated by CCAAT/enhancer-binding protein family members. J Biol Chem. 2003; 279(4):2559-67. DOI: 10.1074/jbc.M308809200. View

18.

Hirota K, Duarte J, Veldhoen M, Hornsby E, Li Y, Cua D . Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011; 12(3):255-63. PMC: 3040235. DOI: 10.1038/ni.1993. View

19.

Screpanti I, Romani L, Musiani P, Modesti A, Fattori E, Lazzaro D . Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice. EMBO J. 1995; 14(9):1932-41. PMC: 398292. DOI: 10.1002/j.1460-2075.1995.tb07185.x. View

20.

McGeachy M, Chen Y, Tato C, Laurence A, Joyce-Shaikh B, Blumenschein W . The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 2009; 10(3):314-24. PMC: 2945605. DOI: 10.1038/ni.1698. View