Antimicrobial and immunoregulatory effector mechanisms in human endothelial cells

Däubener, Walter; Schmidt, Silvia K.; Heseler, Kathrin; Spekker, Katrin; MacKenzie, Colin R.

doi:10.1160/th09-04-0250

Cited by 31 publications

(19 citation statements)

References 64 publications

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“…Previous studies have also found expression of IDO in endothelial cells (ECs) (28, 29). We similarly found that CD31 + ECs in lesional skin colocalized with both IDO and KYNU (Figure 2G).…”

Section: Resultsmentioning

confidence: 93%

The tryptophan metabolism enzyme L-kynureninase is a novel inflammatory factor in psoriasis and other inflammatory diseases

Harden

Lewis

Lish

et al. 2016

Journal of Allergy and Clinical Immunology

128

121

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Background Many human diseases arise from or have pathogenic contributions from a dysregulated immune response. One pathway with immunomodulatory ability is the tryptophan metabolism pathway, which promotes immune suppression via the enzyme indoleamine 2,3 dioxygenase (IDO) and subsequent production of kynurenine. However, in chronic inflammatory skin disease such as psoriasis and atopic dermatitis, another tryptophan metabolism enzyme downstream of IDO, L-kynureninase (KYNU), is heavily upregulated. The role of KYNU has not been explored in these skin diseases, or in general human immunology. Objective To explore the expression and potential immunological function of the tryptophan metabolism enzyme, L-kynureninase, in inflammatory skin disease and its potential contribution to general human immunology. Methods Psoriatic skin biopsies, as well as normal human skin, blood, and primary cells were used to investigate the immunological role of KYNU and tryptophan metabolites. Results Here we show that KYNU+ cells, predominantly of myeloid origin, infiltrate psoriatic lesional skin. KYNU expression positively correlates with disease severity and inflammation, and is reduced upon successful treatment of psoriasis or atopic dermatitis. Tryptophan metabolites downstream of KYNU upregulate several cytokines, chemokines, and cell adhesions. By mining data on several human diseases, we found that in cancers, IDO is preferentially upregulated compared to KYNU, whereas in inflammatory diseases such as atopic dermatitis, KYNU is preferentially upregulated compared to IDO. Conclusion Our results suggest that tryptophan metabolism may dichotomously modulate immune responses, with KYNU as a switch between immunosuppressive versus inflammatory outcomes. Although tryptophan metabolism is increased in many human diseases, how tryptophan metabolism is proceeding may qualitatively affect the immune response in that disease.

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“…Previous studies have also found expression of IDO in endothelial cells (ECs) (28, 29). We similarly found that CD31 + ECs in lesional skin colocalized with both IDO and KYNU (Figure 2G).…”

Section: Resultsmentioning

confidence: 93%

The tryptophan metabolism enzyme L-kynureninase is a novel inflammatory factor in psoriasis and other inflammatory diseases

Harden

Lewis

Lish

et al. 2016

Journal of Allergy and Clinical Immunology

128

121

View full text Add to dashboard Cite

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“…In many though not all situations, addition of exogenous l -Trp attenuates growth inhibition, consistent with the notion that limitation of this essential amino acid by IDO1 at least in part explains the antimicrobial activity observed. The antimicrobial activity of IDO1 in human endothelial cells has been reviewed recently (81). …”

Section: Role Of Trp Degradationmentioning

confidence: 99%

“…In situations where pro-inflammatory stimuli act on and induce MHC-II expression in placental endothelial cells, the ensuing immune response may, however, be modulated by endothelial IDO1. An antibacterial and antiparasitic role of endothelial IDO1 may be anticipated, and this might contribute to protection of the feto-placental unit against infection (81). …”

Section: Role Of Trp Degradationmentioning

confidence: 99%

The Role of Placental Tryptophan Catabolism

2014

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This review discusses the mechanisms and consequences of degradation of tryptophan (Trp) in the placenta, focusing mainly on the role of indoleamine 2,3-dioxygenase-1 (IDO1), one of three enzymes catalyzing the first step of the kynurenine pathway of Trp degradation. IDO1 has been implicated in regulation of feto-maternal tolerance in the mouse. Local depletion of Trp and/or the presence of metabolites of the kynurenine pathway mediate immunoregulation and exert antimicrobial functions. In addition to the decidual glandular epithelium, IDO1 is localized in the vascular endothelium of the villous chorion and also in the endothelium of spiral arteries of the decidua. Possible consequences of IDO1-mediated catabolism of Trp in the endothelium encompass antimicrobial activity and immunosuppression, as well as relaxation of the placental vasotonus, thereby contributing to placental perfusion and growth of both placenta and fetus. It remains to be evaluated whether other enzymes mediating Trp oxidation, such as indoleamine 2,3-dioxygenase-2, Trp 2,3-dioxygenase, and Trp hydroxylase-1 are of relevance to the biology of the placenta.

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“…2 IDO has immunologic functions. In the initial stage of some infectious diseases it can, by depleting TRP, inhibit the growth of the pathogens 3 and thereby disease progression. In the later stages, IDO may be involved in regulating immune responses and creating immune tolerance, acting as a protective feedback mechanism against an overzealous T-cell response.…”

mentioning

confidence: 99%

“…A number of hyperglycemia- and dyslipidemia-activated pathways leading to retinal endothelial cell and neural cell dysfunction have been identified. 3–21 Thus, the loss of neurons is also observed as part of the pathophysiology 22–29 ; ultimately the summation of these aberrant events can lead to vision loss and even blindness.…”

mentioning

confidence: 99%

Increased Indoleamine 2,3-Dioxygenase and Quinolinic Acid Expression in Microglia and Müller Cells of Diabetic Human and Rodent Retina

Hunt

Arfuso

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeWe investigated the relationship between inflammation, neuronal loss, and expression of indoleamine 2, 3-dioxygenase (IDO) and quinolinic acid (QUIN) in the retina of subjects with type 1 diabetes (T1D) and type 2 diabetes (T2D) and in the retina of rats with T1D.MethodsRetinas from T1D (n = 7), T2D (n = 13), and 20 age-matched nondiabetic human donors and from T1D (n = 3) and control rats (n = 3) were examined using immunohistochemistry for IDO, QUIN, cluster of differentiation 39 (CD39), ionized calcium-binding adaptor molecule (Iba-1, for macrophages and microglia), Vimentin (VIM; for Müller cells), neuronal nuclei (NeuN; for neurons), and UEA1 lectin (for blood vessels).ResultsBased on morphologic criteria, CD39+/ionized calcium binding adaptor molecule 1(Iba-1+) resident microglia and CD39−/Iba-1+ bone marrow–derived macrophages were present at higher density in T1D (13% increase) and T2D (26% increase) human retinas when compared with controls. The density and brightness of IDO+ microglia were increased in both T1D and T2D human retinas. The intensity of QUIN+ expression on CD39+ microglia and VIM+ Müller cells was greatly increased in both human T1D and T2D retinas. T1D retinas showed a 63% loss of NeuN+ neurons and T2D retinas lost approximately 43% when compared with nondiabetic human retinas. Few QUIN+ microglia-like cells were seen in nondiabetic retinas, but the numbers increased 18-fold in T1D and 7-fold in T2D in the central retina. In T1D rat retinas, the density of IDO+ microglia increased 2.8-fold and brightness increased 2.1-fold when compared with controls.ConclusionsOur findings suggest that IDO and QUIN expression in the retinas of diabetic rats and humans could contribute to the neuronal degeneration that is characteristic of diabetic retinopathy.

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Antimicrobial and immunoregulatory effector mechanisms in human endothelial cells

Cited by 31 publications

References 64 publications

The tryptophan metabolism enzyme L-kynureninase is a novel inflammatory factor in psoriasis and other inflammatory diseases

The tryptophan metabolism enzyme L-kynureninase is a novel inflammatory factor in psoriasis and other inflammatory diseases

The Role of Placental Tryptophan Catabolism

Increased Indoleamine 2,3-Dioxygenase and Quinolinic Acid Expression in Microglia and Müller Cells of Diabetic Human and Rodent Retina

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