AUTHOR=Mannarino Massimo R. , Bianconi Vanessa , Scalisi Giulia , Franceschini Luca , Manni Giorgia , Cucci Alessia , Bagaglia Francesco , Mencarelli Giulia , Giglioni Francesco , Ricciuti Doriana , Figorilli Filippo , Pieroni Benedetta , Cosentini Elena , Padiglioni Eleonora , Colangelo Cecilia , Fuchs Dietmar , Puccetti Paolo , Follenzi Antonia , Pirro Matteo , Gargaro Marco , Fallarino Francesca TITLE=A tryptophan metabolite prevents depletion of circulating endothelial progenitor cells in systemic low-grade inflammation JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.964660 DOI=10.3389/fimmu.2023.964660 ISSN=1664-3224 ABSTRACT=Background

Chronic systemic inflammation reduces the bioavailability of circulating endothelial progenitor cells (EPCs). Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme of immune tolerance catalyzing the initial step of tryptophan degradation along the so-called l-kynurenine (l-kyn) pathway, that is induced by inflammatory stimuli and exerts anti-inflammatory effects. A specific relationship between IDO1 activity and circulating EPC numbers has not yet been investigated.

Methods

In this study, circulating EPCs were examined in mice treated with low doses of lipopolysaccharide (LPS) to mimic low-grade inflammation. Moreover, the association between IDO1 activity and circulating EPCs was studied in a cohort of 277 patients with variable systemic low-grade inflammation.

Results

Repeated low doses of LPS caused a decrease in circulating EPCs and l-kyn supplementation, mimicking IDO1 activation, significantly increased EPC numbers under homeostatic conditions preventing EPC decline in low-grade endotoxemia. Accordingly, in patients with variable systemic low-grade inflammation, there was a significant interaction between IDO1 activity and high-sensitivity C-reactive protein (hs-CRP) in predicting circulating EPCs, with high hs-CRP associated with significantly lower EPCs at low IDO1 activity but not at high IDO1 activity.

Interpretation

Overall, these findings demonstrate that systemic low-grade inflammation reduces circulating EPCs. However, high IDO1 activity and l-kyn supplementation limit circulating EPC loss in low-grade inflammation.