A Helminth Immunomodulator Exploits Host Signaling Events to Regulate Cytokine Production in Macrophages

PLoS Pathogens

Thomas Ziegler¹  Susanne Hartmann¹  Christian Klotz¹  Sebastian Rausch¹  Matthew R. Hepworth¹  Richard Lucius¹  Nadja Obsivac¹  Peter Hammerstein²  Ana Sofia Figueiredo²  Roland Lang³  Christine Sers⁴ 

[1] Department of Molecular Parasitology, Humboldt-University Berlin, Berlin, Germany;Institute for Theoretical Biology, Humboldt-University Berlin, Berlin, Germany;Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Erlangen, Germany;Institute of Pathology, Charite Universtitätsmedizin Berlin, Berlin, Germany

关键词: Macrophages;    MAPK signaling cascades;    Cytokines;    Phosphorylation;    Mathematical models;    ERK signaling cascade;    Flow cytometry;    Transcription factors;   

DOI  :  10.1371/journal.ppat.1001248

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Parasitic worms alter their host's immune system to diminish the inflammatory responses directed against them, using very efficient immunomodulating molecules. We have previously shown that the helminth immunomodulator cystatin (AvCystatin) profoundly reduces the progression of inflammatory diseases via modulation of macrophages. Here we elucidate the signaling events in macrophages triggered by AvCystatin. Labeled AvCystatin was predominantly taken up by macrophages and subsequently induced the phosphorylation of the mitogen-activated protein kinases (MAPK) ERK1/2 and p38. IL-10 expression induced by AvCystatin in macrophages was tyrosine kinase sensitive and dependent on activation of both MAP kinases, in clear contrast to expression of IL-12/23p40. In addition, phosphorylation of the transcription factors CREB and STAT3 was induced by AvCystatin and regulated by phospho-ERK. Chemical inhibition of phosphoinositide 3-kinase (PI3K) reduced AvCystatin-induced cytokine release; however, AKT, the downstream target of PI3K, was not activated following AvCystatin exposure. To characterize signaling elements involved in alteration of the macrophage phenotype we applied mathematical modeling. Experimental testing of the in silico generated hypotheses identified dual specificity phosphatase (DUSP) 1 and 2, as regulators in AvCystatin triggered macrophages in vitro and in vivo. In particular, DUSP1 was subsequently found to be responsible for regulation of ERK- and p38-phosphorylation and controlled the IL-10 expression in macrophages by AvCystatin. Thus, we show that AvCystatin exploits activation and deactivation pathways of MAP kinases to induce regulatory macrophages. This study provides insights into molecular mechanisms of macrophage manipulation by parasites and highlights the utility of mathematical modeling for the elucidation of regulatory circuits of immune cells.

【 授权许可】

CC BY