Limited Effect of Indolamine 2,3-Dioxygenase Expression and Enzymatic Activity on Lupus-Like Disease in B6.Nba2 Mice.

Laura M Davison,Andrew L Mellor,Jessica C Liu,Trine N Jørgensen,Lei Huang,Thomas M Carroll

doi:10.3389/fimmu.2019.02017

Abstract

B6.Nba2 mice spontaneously develop a lupus-like disease characterized by elevated levels of serum anti-nuclear autoantibody (ANA) immune complexes and constitutive type I interferon (IFNα) production. During disease progression, both plasmacytoid dendritic cells (pDCs) and antibody secreting plasma cells accumulate in spleens of B6.Nba2 mice. Indoleamine 2,3-dioxygenase (IDO) has been suggested to play a role in several autoimmune diseases including in the MRL/lpr model of mouse lupus-like disease; however, it remains unknown if IDO is involved in disease development and/or progression in other spontaneous models. We show here that IDO1 protein and total IDO enzymatic activity are significantly elevated in lupus-prone B6.Nba2 mice relative to B6 controls. IDO1 expression was restricted to PCs and SignR1+ macrophages in both strains, while significantly increased in B6.Nba2-derived SiglecH+ (SigH+) pDCs. Despite this unique expression pattern, neither pharmacologic inhibition of total IDO nor IDO1 gene ablation altered serum autoantibody levels, splenic immune cell activation pattern, or renal inflammation in B6.Nba2 mice. Interestingly, IDO pharmacologic inhibition, but not IDO1 deficiency, resulted in diminished complement factor C'3 fixation to kidney glomeruli, suggesting a possible therapeutic benefit of IDO inhibition in SLE patients with renal involvement.

Highlights

Oxidative tryptophan (Trp) degradation is driven via the kynurenine pathway by one of three rate limiting enzymes: tryptophan 2,3-dioxygenase, indoleamine 2,3-dioxygenase (IDO)-1, or IDO2 [1]
IDO1 and IDO2 molecules have been suggested to be expressed by plasmacytoid dendritic cells (CD19+ and SigH+), macrophages (SignR1+), myeloid-derived suppressor cells (MDSCs), and lately B cells and plasma cells [12,13,14,15,16,17,18,19,20,21,22,23]
Since levels of IDO1 protein are not necessarily a direct indication of total IDO enzymatic activity, quick-frozen spleen samples were subsequently tested for total IDO enzymatic activity in an in vitro tryptophan (Trp) catabolism assay [40]

Summary

Introduction

Oxidative tryptophan (Trp) degradation is driven via the kynurenine pathway by one of three rate limiting enzymes: tryptophan 2,3-dioxygenase, indoleamine 2,3-dioxygenase (IDO)-1, or IDO2 [1]. Induction of IDO activity depletes the local environment of Trp, triggering the general amino acid control non-depressible 2 (GCN2) stress pathway preventing T cell proliferation and inducing anergy [2,3,4,5]. Downstream metabolites of IDO enzymatic activity such as 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QA) have been shown to induce the generation, and support the maintenance, of regulatory T cells (Tregs) [6, 7]. In addition to a role in T cell differentiation and activity, recent studies have suggested that IDO1 and/or IDO2 may control humoral immunity via B-cell intrinsic mechanisms [17, 24]

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