Kynurenine, Tetrahydrobiopterin, and Cytokine Inflammatory Biomarkers in Individuals Affected by Diabetic Neuropathic Pain

Ananda Staats Pires, Benjamin Heng, Vanessa X Tan, Alexandra Latini, Marc A Russo, Danielle M Santarelli, Dominic Bailey, Katie Wynne, Jayden A O'Brien, Gilles J Guillemin, Paul J Austin, Ananda Staats Pires, Benjamin Heng, Vanessa X Tan, Alexandra Latini, Marc A Russo, Danielle M Santarelli, Dominic Bailey, Katie Wynne, Jayden A O'Brien, Gilles J Guillemin, Paul J Austin

Abstract

Neuropathic pain is a common complication of diabetes with high morbidity and poor treatment outcomes. Accumulating evidence suggests the immune system is involved in the development of diabetic neuropathy, whilst neuro-immune interactions involving the kynurenine (KYN) and tetrahydrobiopterin (BH4) pathways have been linked to neuropathic pain pre-clinically and in several chronic pain conditions. Here, using a multiplex assay, we quantified serum levels of 14 cytokines in 21 participants with type 1 diabetes mellitus, 13 of which were classified as having neuropathic pain. In addition, using high performance liquid chromatography and gas chromatography-mass spectrometry, all major KYN and BH4 pathway metabolites were quantified in serum from the same cohort. Our results show increases in GM-CSF and IL-8, suggesting immune cell involvement. We demonstrated increases in two inflammatory biomarkers: neopterin and the KYN/TRP ratio, a marker of indoleamine 2,3-dioxygenase activity. Moreover, the KYN/TRP ratio positively correlated with pain intensity. Total kynurenine aminotransferase activity was also higher in the diabetic neuropathic pain group, indicating there may be increased production of the KYN metabolite, xanthurenic acid. Overall, this study supports the idea that inflammatory activation of the KYN and BH4 pathways occurs due to elevated inflammatory cytokines, which might be involved in the pathogenesis of neuropathic pain in type 1 diabetes mellitus. Further studies should be carried out to investigate the role of KYN and BH4 pathways, which could strengthen the case for therapeutically targeting them in neuropathic pain conditions.

Keywords: kynurenine; neuropathic pain; pro-inflammatory cytokines; tetrahydrobiopterin; type 1 diabetes.

Copyright © 2020 Staats Pires, Heng, Tan, Latini, Russo, Santarelli, Bailey, Wynne, O’Brien, Guillemin and Austin.

Figures

FIGURE 1
FIGURE 1
A schematic diagram of the kynurenine (KYN) and tetrahydrobiopterin (BH4) pathways. Both KYN and BH4 pathways are activated by inflammatory cytokines such as IL-1β, Il-6, IFN-γ, TNF-α, and the immune activator LPS. LPS, lipopolysaccharide; GTP, Guanosine-5’-triphosphate; GTPCH, GTP cyclohydrolase I; PTPS, 6-pyruvoyl-tetrahydropterin synthase; IDO, Indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; KATs, Kynurenine aminotransferases; KYNA, Kynurenine acid; XA, Xanthurenic acid; KYNU, Kynureninase; AA, Anthranilic acid; KMO, Kynurenine 3-monooxygenase; 3-HK, 3-Hydroxykynurenine; 3-HAA, 3-Hydroxyanthranilic acid; 3-HAO, 3-hydroxyanthranilate 3,4-dioxygenase; QUIN, Quinolinic acid.
FIGURE 2
FIGURE 2
Cytokine levels in the serum of diabetic neuropathic pain and diabetic control groups. (A) GM-CSF and (B) IL-8 in serum of DNP participants and diabetic controls. *P < 0.05, **P < 0.01, unpaired two-tailed Mann–Whitney U-test. Circles represent male participants; triangles represent female participants.
FIGURE 3
FIGURE 3
Levels of two major inflammatory biomarkers in the serum of diabetic neuropathic pain and diabetes control groups. (A) KYN/TRP ratio and (B) NEO in serum of DNP participants and diabetic controls. *P < 0.05, unpaired two-tailed Student’s T-test. (C) The relationship between pain intensity score and the KYN/TRP ratio in DNP and DC groups. *P < 0.05 & R2 linear regression analysis. Circles represent male participants; triangles represent female participants. TRP, Tryptophan; KYN, Kynurenine; NEO, neopterin; VAS, Visual analog scale.
FIGURE 4
FIGURE 4
The relationships between TNF-α and IL-1β, and metabolites of the KYN and BH4 pathways in serum of diabetic neuropathic pain and diabetic control groups. (A) TNF-α and KYN expression correlate in the DNP group. (B) TNF-α and PIC expression correlate in the DNP group. (C) IL-1β and BH4 levels correlate in the DNP group. **P < 0.01, P < 0.001 & R2 from linear regression analysis. Circles represent male participants; triangles represent female participants.

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