Differential control of Mincle-dependent cord factor recognition and macrophage responses by the transcription factors C/EBP? and HIF1?

Schoenen HG, Huber A, Sonda N, Zimmermann S, Jantsch J, Lepenies B, Bronte V, Lang R (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Journal of Immunology American Association of Immunologists

Publisher: American Association of Immunologists

Book Volume: 193

Pages Range: 3664-75

Journal Issue: 7

DOI: 10.4049/jimmunol.1301593

Abstract

Trehalose-6,6-dimycolate (TDM), the mycobacterial cord factor, and its synthetic analog Trehalose-6,6-dibehenate (TDB) bind to the C-type lectin receptors macrophage-inducible C-type lectin (Mincle) and Mcl to activate macrophages. Genetically, the transcriptional response to TDB/TDM has been defined to require FcR?-Syk-Card9 signaling. However, TDB/TDM-triggered kinase activation has not been studied well, and it is largely unknown which transcriptional regulators bring about inflammatory gene expression. In this article, we report that TDB/TDM caused only weak Syk-phosphorylation in resting macrophages, consistent with low basal Mincle expression. However, LPS-priming caused MYD88-dependent upregulation of Mincle, resulting in enhanced TDB/TDM-induced kinase activation and more rapid inflammatory gene expression. TLR-induced Mincle expression partially circumvented the requirement for Mcl in the response to TDB/TDM. To dissect transcriptional responses to TDB/TDM, we mined microarray data and identified early growth response (Egr) family transcription factors as direct Mincle target genes, whereas upregulation of Cebpb and Hif1a required new protein synthesis. Macrophages and dendritic cells lacking C/EBP? showed nearly complete abrogation of TDB/TDM responsiveness, but also failed to upregulate Mincle. Retroviral rescue of Mincle expression in Cebpb-deficient cells restored induction of Egr1, but not of G-CSF. This pattern of C/EBP? dependence was also observed after stimulation with the Dectin-1 ligand Curdlan. Inducible expression of hypoxia-inducible factor 1? (HIF1?) also required C/EBP?. In turn, HIF1? was not required for Mincle expression, kinase activation, and Egr1 or Csf3 expression, but critically contributed to NO production. Taken together, we identify C/EBP? as central hub in Mincle expression and inflammatory gene induction, whereas HIF1? controls Nos2 expression. C/EBP? also connects TLR signals to cord factor responsiveness through MYD88-dependent upregulation of Mincle.

Authors with CRIS profile

Hanne Gunda Schoenen Lehrstuhl für Biochemie Alexandra Huber Professur für Mikrobiologie Roland Lang Professur für Angeborene Immunität und Pathogenerkennung

Involved external institutions

University of Padua / Universita degli Studi di Padova IT Italy (IT) Freie Universität Berlin DE Germany (DE) University of Verona / Università degli Studi di Verona IT Italy (IT)

How to cite

APA:

Schoenen, H.G., Huber, A., Sonda, N., Zimmermann, S., Jantsch, J., Lepenies, B.,... Lang, R. (2014). Differential control of Mincle-dependent cord factor recognition and macrophage responses by the transcription factors C/EBP? and HIF1? Journal of Immunology, 193(7), 3664-75. https://doi.org/10.4049/jimmunol.1301593

MLA:

Schoenen, Hanne Gunda, et al. "Differential control of Mincle-dependent cord factor recognition and macrophage responses by the transcription factors C/EBP? and HIF1?" Journal of Immunology 193.7 (2014): 3664-75.

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