Skip to main content
Top
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

CCAAT/enhancer-binding protein δ (C/EBPδ) aggravates inflammation and bacterial dissemination during pneumococcal meningitis

Authors: Mercedes Valls Serón, JanWillem Duitman, Madelijn Geldhoff, JooYeon Engelen-Lee, Stefan R Havik, Matthijs C Brouwer, Diederik van de Beek, C Arnold Spek

Published in: Journal of Neuroinflammation | Issue 1/2015

Login to get access

Abstract

Background

The prognosis of bacterial meningitis largely depends on the severity of the inflammatory response. The transcription factor CAAT/enhancer-binding protein δ (C/EBPδ) plays a key role in the regulation of the inflammatory response during bacterial infections. Consequently, we assessed the role of C/EBPδ during experimental meningitis.

Methods

Wild-type and C/EBPδ-deficient mice (C/EBPδ−/−) were intracisternally infected with Streptococcus pneumoniae and sacrificed after 6 or 30 h, or followed in a survival study.

Results

In comparison to wild-type mice, C/EBPδ−/− mice showed decreased bacterial loads at the primary site of infection and decreased bacterial dissemination to lung and spleen 30 h after inoculation. Expression levels of the inflammatory mediators IL-10 and KC were lower in C/EBPδ−/− brain homogenates, whereas IL-6, TNF-α, IL-1β, and MIP-2 levels were not significantly different between the two genotypes. Moreover, C/EBPδ−/− mice demonstrated an attenuated systemic response as reflected by lower IL-10, IL-6, KC, and MIP-2 plasma levels. No differences in clinical symptoms or in survival were observed between wild-type and C/EBPδ−/− mice.

Conclusion

C/EBPδ in the brain drives the inflammatory response and contributes to bacterial dissemination during pneumococcal meningitis. C/EBPδ does, however, not affect clinical parameters of the disease and does not confer a survival benefit.
Literature
1.
go back to reference van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet. 2012;380:1693–702.CrossRefPubMed van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet. 2012;380:1693–702.CrossRefPubMed
2.
go back to reference McIntyre PB, O’Brien KL, Greenwood B, van de Beek D. Effect of vaccines on bacterial meningitis worldwide. Lancet. 2012;380:1703–11.CrossRefPubMed McIntyre PB, O’Brien KL, Greenwood B, van de Beek D. Effect of vaccines on bacterial meningitis worldwide. Lancet. 2012;380:1703–11.CrossRefPubMed
3.
go back to reference van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. New Engl J Med. 2004;351:1849–59.CrossRefPubMed van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. New Engl J Med. 2004;351:1849–59.CrossRefPubMed
4.
go back to reference Brouwer MC, Tunkel AR, van de Beek D. Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clin Microbiol Rev. 2010;23:467–92.CrossRefPubMedCentralPubMed Brouwer MC, Tunkel AR, van de Beek D. Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clin Microbiol Rev. 2010;23:467–92.CrossRefPubMedCentralPubMed
5.
go back to reference Scheld WM, Koedel U, Nathan B, Pfister HW. Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. J Infect Dis. 2002;186 Suppl 2:S225–33.CrossRefPubMed Scheld WM, Koedel U, Nathan B, Pfister HW. Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. J Infect Dis. 2002;186 Suppl 2:S225–33.CrossRefPubMed
7.
go back to reference Mook-Kanamori BB, Geldhoff M, van der Poll T, van de Beek D. Pathogenesis and pathophysiology of pneumococcal meningitis. Clin Microbiol Rev. 2011;24:557–91.CrossRefPubMedCentralPubMed Mook-Kanamori BB, Geldhoff M, van der Poll T, van de Beek D. Pathogenesis and pathophysiology of pneumococcal meningitis. Clin Microbiol Rev. 2011;24:557–91.CrossRefPubMedCentralPubMed
9.
go back to reference Tengku-Muhammad TS, Hughes TR, Ranki H, Cryer A, Ramji DP. Differential regulation of macrophage CCAAT-enhancer binding protein isoforms by lipopolysaccharide and cytokines. Cytokine. 2000;12:1430–6.CrossRefPubMed Tengku-Muhammad TS, Hughes TR, Ranki H, Cryer A, Ramji DP. Differential regulation of macrophage CCAAT-enhancer binding protein isoforms by lipopolysaccharide and cytokines. Cytokine. 2000;12:1430–6.CrossRefPubMed
10.
go back to reference Alam T, An MR, Papaconstantinou J. Differential expression of three C/EBP isoforms in multiple tissues during the acute phase response. J Biol Chem. 1992;267:5021–4.PubMed Alam T, An MR, Papaconstantinou J. Differential expression of three C/EBP isoforms in multiple tissues during the acute phase response. J Biol Chem. 1992;267:5021–4.PubMed
11.
go back to reference Kinoshita S, Akira S, Kishimoto T. A member of the C/EBP family, NF-IL6 beta, forms a heterodimer and transcriptionally synergizes with NF-IL6. Proc Natl Acad Sci U S A. 1992;89:1473–6.CrossRefPubMedCentralPubMed Kinoshita S, Akira S, Kishimoto T. A member of the C/EBP family, NF-IL6 beta, forms a heterodimer and transcriptionally synergizes with NF-IL6. Proc Natl Acad Sci U S A. 1992;89:1473–6.CrossRefPubMedCentralPubMed
12.
go back to reference Litvak V, Ramsey SA, Rust AG, Zak DE, Kennedy KA, Lampano AE, et al. Function of C/EBPdelta in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals. Nature Immun. 2009;10:437–43.CrossRefPubMedCentralPubMed Litvak V, Ramsey SA, Rust AG, Zak DE, Kennedy KA, Lampano AE, et al. Function of C/EBPdelta in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals. Nature Immun. 2009;10:437–43.CrossRefPubMedCentralPubMed
13.
go back to reference Duitman J, Hoogendijk AJ, Groot AP, Ruela de Sousa RR, van der Poll T, Florquin S, et al. CCAAT-enhancer binding protein delta (C/EBPdelta) protects against Klebsiella pneumoniae-induced pulmonary infection: potential role for macrophage migration. J Infect Dis. 2012;206:1826–35.CrossRefPubMed Duitman J, Hoogendijk AJ, Groot AP, Ruela de Sousa RR, van der Poll T, Florquin S, et al. CCAAT-enhancer binding protein delta (C/EBPdelta) protects against Klebsiella pneumoniae-induced pulmonary infection: potential role for macrophage migration. J Infect Dis. 2012;206:1826–35.CrossRefPubMed
14.
go back to reference Duitman J, Schouten M, Groot AP, Borensztajn KS, Daalhuisen JB, Florquin S, et al. CCAAT/enhancer-binding protein delta facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner. Proc Natl Acad Sci U S A. 2012;109:9113–8.CrossRefPubMedCentralPubMed Duitman J, Schouten M, Groot AP, Borensztajn KS, Daalhuisen JB, Florquin S, et al. CCAAT/enhancer-binding protein delta facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner. Proc Natl Acad Sci U S A. 2012;109:9113–8.CrossRefPubMedCentralPubMed
15.
go back to reference Duitman J, Teske GJ, Butter LM, Leemans JC, Florquin S, Spek CA. CCAAT/enhancer-binding protein delta (C/EBPdelta) plays a minor role in renal host defense against uropathogenic Escherichia coli. Transplant Infec Dis. 2013;15:E119–21.CrossRef Duitman J, Teske GJ, Butter LM, Leemans JC, Florquin S, Spek CA. CCAAT/enhancer-binding protein delta (C/EBPdelta) plays a minor role in renal host defense against uropathogenic Escherichia coli. Transplant Infec Dis. 2013;15:E119–21.CrossRef
16.
go back to reference Sterneck E, Paylor R, Jackson-Lewis V, Libbey M, Przedborski S, Tessarollo L, et al. Selectively enhanced contextual fear conditioning in mice lacking the transcriptional regulator CCAAT/enhancer binding protein delta. Proc Natl Acad Sci U S A. 1998;95:10908–13.CrossRefPubMedCentralPubMed Sterneck E, Paylor R, Jackson-Lewis V, Libbey M, Przedborski S, Tessarollo L, et al. Selectively enhanced contextual fear conditioning in mice lacking the transcriptional regulator CCAAT/enhancer binding protein delta. Proc Natl Acad Sci U S A. 1998;95:10908–13.CrossRefPubMedCentralPubMed
17.
go back to reference Mook-Kanamori B, Geldhoff M, Troost D, van der Poll T, van de Beek D. Characterization of a pneumococcal meningitis mouse model. BMC Infect Dis. 2012;12:71.CrossRefPubMedCentralPubMed Mook-Kanamori B, Geldhoff M, Troost D, van der Poll T, van de Beek D. Characterization of a pneumococcal meningitis mouse model. BMC Infect Dis. 2012;12:71.CrossRefPubMedCentralPubMed
18.
go back to reference Slofstra SH, Bijlsma MF, Groot AP, Reitsma PH, Lindhout T, ten Cate H, et al. Protease-activated receptor-4 inhibition protects from multiorgan failure in a murine model of systemic inflammation. Blood. 2007;110:3176–82.CrossRefPubMed Slofstra SH, Bijlsma MF, Groot AP, Reitsma PH, Lindhout T, ten Cate H, et al. Protease-activated receptor-4 inhibition protects from multiorgan failure in a murine model of systemic inflammation. Blood. 2007;110:3176–82.CrossRefPubMed
19.
go back to reference Arsenijevic T, Gregoire F, Delforge V, Delporte C, Perret J. Murine 3T3-L1 adipocyte cell differentiation model: validated reference genes for qPCR gene expression analysis. PLoS One. 2012;7, e37517.CrossRefPubMedCentralPubMed Arsenijevic T, Gregoire F, Delforge V, Delporte C, Perret J. Murine 3T3-L1 adipocyte cell differentiation model: validated reference genes for qPCR gene expression analysis. PLoS One. 2012;7, e37517.CrossRefPubMedCentralPubMed
20.
go back to reference Bergeron Y, Ouellet N, Deslauriers AM, Simard M, Olivier M, Bergeron MG. Cytokine kinetics and other host factors in response to pneumococcal pulmonary infection in mice. Infect Immun. 1998;66:912–22.PubMedCentralPubMed Bergeron Y, Ouellet N, Deslauriers AM, Simard M, Olivier M, Bergeron MG. Cytokine kinetics and other host factors in response to pneumococcal pulmonary infection in mice. Infect Immun. 1998;66:912–22.PubMedCentralPubMed
21.
go back to reference Knapp S, Schultz MJ, van der Poll T. Pneumonia models and innate immunity to respiratory bacterial pathogens. Shock. 2005;24 Suppl 1:12–8.CrossRefPubMed Knapp S, Schultz MJ, van der Poll T. Pneumonia models and innate immunity to respiratory bacterial pathogens. Shock. 2005;24 Suppl 1:12–8.CrossRefPubMed
22.
go back to reference Yan C, Johnson PF, Tang H, Ye Y, Wu M, Gao H. CCAAT/enhancer-binding protein delta is a critical mediator of lipopolysaccharide-induced acute lung injury. Am J Pathol. 2013;182:420–30.CrossRefPubMedCentralPubMed Yan C, Johnson PF, Tang H, Ye Y, Wu M, Gao H. CCAAT/enhancer-binding protein delta is a critical mediator of lipopolysaccharide-induced acute lung injury. Am J Pathol. 2013;182:420–30.CrossRefPubMedCentralPubMed
23.
go back to reference Hsiao YW, Li CF, Chi JY, Tseng JT, Chang Y, Hsu LJ, et al. CCAAT/enhancer binding protein delta in macrophages contributes to immunosuppression and inhibits phagocytosis in nasopharyngeal carcinoma. Sci Signal. 2013;6:ra59. Hsiao YW, Li CF, Chi JY, Tseng JT, Chang Y, Hsu LJ, et al. CCAAT/enhancer binding protein delta in macrophages contributes to immunosuppression and inhibits phagocytosis in nasopharyngeal carcinoma. Sci Signal. 2013;6:ra59.
24.
go back to reference Tsai VW, Mohammad MG, Tolhurst O, Breit SN, Sawchenko PE, Brown DA. CCAAT/enhancer binding protein-delta expression by dendritic cells regulates CNS autoimmune inflammatory disease. J Neurosci. 2011;31:17612–21.CrossRefPubMedCentralPubMed Tsai VW, Mohammad MG, Tolhurst O, Breit SN, Sawchenko PE, Brown DA. CCAAT/enhancer binding protein-delta expression by dendritic cells regulates CNS autoimmune inflammatory disease. J Neurosci. 2011;31:17612–21.CrossRefPubMedCentralPubMed
25.
go back to reference Slofstra SH, Groot AP, Obdeijn MH, Reitsma PH, ten Cate H, Spek CA. Gene expression profiling identifies C/EBPdelta as a candidate regulator of endotoxin-induced disseminated intravascular coagulation. Am J Resp Crit Care Med. 2007;176:602–9.CrossRefPubMed Slofstra SH, Groot AP, Obdeijn MH, Reitsma PH, ten Cate H, Spek CA. Gene expression profiling identifies C/EBPdelta as a candidate regulator of endotoxin-induced disseminated intravascular coagulation. Am J Resp Crit Care Med. 2007;176:602–9.CrossRefPubMed
26.
go back to reference Oldekamp S, Pscheidl S, Kress E, Soehnlein O, Jansen S, Pufe T, et al. Lack of formyl peptide receptor 1 and 2 leads to more severe inflammation and higher mortality in mice with of pneumococcal meningitis. Immunology. 2014;143:447–61.CrossRefPubMed Oldekamp S, Pscheidl S, Kress E, Soehnlein O, Jansen S, Pufe T, et al. Lack of formyl peptide receptor 1 and 2 leads to more severe inflammation and higher mortality in mice with of pneumococcal meningitis. Immunology. 2014;143:447–61.CrossRefPubMed
Metadata
Title
CCAAT/enhancer-binding protein δ (C/EBPδ) aggravates inflammation and bacterial dissemination during pneumococcal meningitis
Authors
Mercedes Valls Serón
JanWillem Duitman
Madelijn Geldhoff
JooYeon Engelen-Lee
Stefan R Havik
Matthijs C Brouwer
Diederik van de Beek
C Arnold Spek
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0309-5

Other articles of this Issue 1/2015

Journal of Neuroinflammation 1/2015 Go to the issue