Indoleamine 2,3-dioxygenase–expressing dendritic cells form suppurative granulomas following Listeria monocytogenes infection
Alexey Popov, … , Olaf Utermöhlen, Joachim L. Schultze
Alexey Popov, … , Olaf Utermöhlen, Joachim L. Schultze
Published December 1, 2006
Citation Information: J Clin Invest. 2006;116(12):3160-3170. https://doi.org/10.1172/JCI28996.
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Research Article Immunology

Indoleamine 2,3-dioxygenase–expressing dendritic cells form suppurative granulomas following Listeria monocytogenes infection

Abstract

Control of pathogens by formation of abscesses and granulomas is a major strategy of the innate immune system, especially when effector mechanisms of adaptive immunity are insufficient. We show in human listeriosis that DCs expressing indoleamine 2,3-dioxygenase (IDO), together with macrophages, are major cellular components of suppurative granulomas in vivo. Induction of IDO by DCs is a cell-autonomous response to Listeria monocytogenes infection and was also observed in other granulomatous infections with intracellular bacteria, such as Bartonella henselae. Reporting on our use of the clinically applied anti–TNF-α antibody infliximab, we further demonstrate in vitro that IDO induction is TNF-α dependent. Repression of IDO therefore might result in exacerbation of granulomatous diseases observed during anti–TNF-α therapy. These findings place IDO+ DCs not only at the intersection of innate and adaptive immunity but also at the forefront of bacterial containment in granulomatous infections.

Authors

Alexey Popov, Zeinab Abdullah, Claudia Wickenhauser, Tomo Saric, Julia Driesen, Franz-Georg Hanisch, Eugen Domann, Emma Lloyd Raven, Oliver Dehus, Corinna Hermann, Daniela Eggle, Svenja Debey, Trinad Chakraborty, Martin Krönke, Olaf Utermöhlen, Joachim L. Schultze

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Figure 6

Influence of L. monocytogenes virulence factors on IDO induction.

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Influence of L. monocytogenes virulence factors on IDO induction. ...
immDCs were either infected with the listeria mutants Δhly or prfA or incubated with hk L. monocytogenes for 30 minutes, washed, and subsequently cultured for 2, 6, or 24 hours Alternatively, DCs were treated with purified LTA derived from L. monocytogenes and cultured for 72 hours. Cells and supernatants were then harvested to assess (A) IDO protein expression and tryptophan levels, (B) COX-2 protein expression and PGE metabolite levels, and (C) TNF-α concentration. Mean ± SD from 2 experiments are shown. Asterisk highlights statistically significant comparison (*P < 0.05). Immunoblots are representative of 2 independent experiments. (D) A heat map illustrating the kinetics of gene expression in immDCs treated with hk L. monocytogenes or infected with virulent L. monocytogenes (WT) and corresponding mock-infected controls on a Sentrix Human-6 Expression BeadChip array. Examination of genes showing significant differences in expression levels between control and listeria-infected DCs at 1 of the 3 time points (fold change > 2; absolute difference in signal intensity > 100) yielded 1,444 candidate genes. Absolute expression values of these gene transcripts in all 3 cell subsets were color coded (white, low expression; dark red; high expression); scale of expression values ranged from 0 to 50,000. (E) IDO protein expression in human DCs was assessed by immunoblotting after 72 hours of LTA treatment at indicated concentrations; β-actin was used as loading control and rhIDO as a positive control. Results of 2 representative experiments are shown.