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.

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

“…IFN-g and TNF-a are the main inducers of IDO activation. 5,6 Minocycline has already been shown to block IFN-g-mediated protein kinase C (a/bII) phosphorylation and nuclear translocation of both protein kinase C (a/bII) and IRF-1, 17 which is necessary for IDO activation. It also inhibits nuclear factor k-B and MAP kinase activation, 35 which are both necessary for the synergistic effects of TNF-a and IFN-g on IDO activation.…”

“…This enzyme is induced by proinflammatory cytokines, mainly interferon-g (IFN-g) 5 and tumor-necrosis factor-a (TNF-a). 6,7 When IDO is activated in conditions of chronic inflammation, its degree of activation is correlated to the intensity of depressive symptoms, as observed in cancer patients chronically treated with IFN-a. 8 Acute activation of the peripheral innate immune system in laboratory animals, through the administration of the cytokine inducer lipopolysaccharide (LPS), induces depressive-like behavior, as measured by increased immobility in the forced-swim test (FST) and tail suspension test (TST), decreased consumption of a sweetened solution and a suppression of sexual behavior, 9,10 which can be attenuated by chronic antidepressant administration.…”

IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

“…Expression of IFN-γ and IL-4 are found simultaneously in the brain in human neurocysticercosis and mouse cryptocococcal meningoencephalitis (Maffei et al 2004;Restrepo et al 2001). IDO expressing cells are indeed present in granulomatous inflammation (Popov et al 2006). Since granuloma formation allows for control of the pathogen, IDO-mediated T cell inhibition can actually protect the host from the untoward consequences of harmful immune reactivity (Zganiacz et al 2004).…”

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

“…IDO has been implicated in tolerance and immunosuppression as it consumes the essential amino acid tryptophan, causing immune somnolence by promoting a semi-matured tolerogenic state on DCs, effector T cell anergy and expansion of Tregs at the site of IDO secretion [72][73][74][75][76]. IDO-expressing regDCs found at the tumor site and in tumor-draining lymph nodes [77][78][79] might help suppress the initiation of immune responses to tumor-derived antigens and perhaps help create systemic tolerance to these antigens [80,81]. Therefore, expression of IDO in regDCs represents a key mechanism responsible for inducing the tolerogenic state.…”