Is the kynurenic acid responsive Gpr35 involved in the ME pathomechanism?

The ME hypothesis "the metabolic trap" tell us that IDO function in immune cells may be compromised (1).

IDO1 and IDO2 catalyze the first step in the kynurenine pathway: The conversion of tryptophan to N-formyl-kynurenine.  N-formyl-kynurenine can be converted to kynurenine (KYN). KYN can be further processed to kynurenic acid (KYNA).

Germain et al showed decreased levels of L-kynurenine / Formyl-5-hydroxykynurenamine in plasma from ME patients (2). Is the KYNA plasma level changed in ME patients?

Agudelo et al have shown (in mice) that kynurenic acid increases energy utilization by activating G protein-coupled receptor Gpr35, which stimulates lipid metabolism, thermogenic, and anti-inflammatory gene expression in adipose tissue.  Kynurenic acid and Gpr35 enhance Pgc-1α1 expression and cellular respiration, and increase the levels of Rgs14 in adipocytes, which leads to enhanced beta-adrenergic receptor signaling (3).

Furthermore, KYNA has been reported to have anti-inflammatory properties and to modulate cytokine release from invariant natural killer T (iNKT) cells through Gpr35 activation (4).

ME patients show alterations in expression of iNKT phenotypes (5, 6).

The gene GPR35 is hypomethylated in peripheral blood mononuclear cells (PBMC) from ME patients (p-value = 6,44E-08, FDR = 0,0029) (7).

Gpr35 is an interesting receptor, it also interacts with the sodium potassium pump. The sodium potassium pump (Na/K-ATPase) ensures the electrochemical gradient of a cell through an energy-dependent process that consumes about one-third of regenerated ATP. Schneditz et al. report that Gpr35 interacts with the α chain of Na/K-ATPase and promotes its ion transport and Src signaling activity in a ligand-independent manner (8).

Is the kynurenic acid responsive Gpr35 involved in the ME pathomechanism?

References:

1) Metabolic Traps in ME/CFS - Research Update by Dr. Robert Phair 
https://www.youtube.com/watch?v=Quh-77gvw4Q

2) Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371 https://pubs.rsc.org/en/Content/ArticleLanding/2017/MB/C6MB00600K#!divAbstract

3) Agudelo et al: Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation. Cell Metab. 2018 Feb 6;27(2):378-392.e5. doi: 10.1016/j.cmet.2018.01.004.
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(18)30053-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1550413118300536%3Fshowall%3Dtrue

4) Fallarin et al: Expression of functional GPR35 in human iNKT cells. Biochem Biophys Res Commun. 2010 Jul 30;398(3):420-5. doi: 10.1016/j.bbrc.2010.06.091. Epub 2010 Jun 25.
https://www.ncbi.nlm.nih.gov/pubmed/20651116

5) Ramos er al: Regulatory T, natural killer T and γδ T cells in multiple sclerosis and chronic fatigue syndrome/myalgic encephalomyelitis: a comparison. Asian Pac J Allergy Immunol. 2016 Dec;34(4):300-305. doi: 10.12932/AP0733. https://www.ncbi.nlm.nih.gov/pubmed/27001659

6) Hardcastle et al: J Transl Med. 2015 Sep 14;13:299. doi: 10.1186/s12967-015-0653-3.
Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. https://www.ncbi.nlm.nih.gov/pubmed/26370228
7) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.
Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

7) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.
Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

8) Schneditz et al. GPR35 promotes glycolysis, proliferation, and oncogenic signaling by engaging with the sodium potassium pump. Sci Signal. 2019 Jan 1;12(562). pii: eaau9048. doi: 10.1126/scisignal.aau9048. https://www.ncbi.nlm.nih.gov/pubmed/30600262