Genomics, proteomics and transcriptomics show the iNOS pathway is upregulated in ME

Activated macrophages produce an inducible NO synthase (iNOS or NOS2).  Although iNOS was originally identified and characterized in macrophages, it is present in numerous cell types including endothelial cells, fibroblasts, vascular smooth muscle cells and cardiac myocytes (1).

Genomics in ME

A gene variant of iNOS has been identified as a risk locus in ME (2):

Slide from. Whole Genome Sequencing and Analysis of ME/CFS

https://www.youtube.com/watch?v=nIJX-Q7w_Z4 

Proteomics in ME

The pathway "Production of NO and ROS in macrophages" was upregulated in the cerebrospinal fluid from ME patients (table S6 in ref 3).

Transcriptomics in ME

Functional Network Analysys of gene transcripts from ME immune cells showed thar the pathway "Production of NO and ROS in macrophages" was enriched (p-value = 0,000018) (4).

Macrophages and the ME-IDO-metabolic trap

The ME-IDO metabolic trap hypothesis tell us that the kynurenic pathway may be blocked in dendritic cells and macrophages. This means decreased metabolites from the pathway (5).

During inflammation and resolution of inflammation, this may be going on in normal cells (6) :

• Increased IDO activity
• Increased kynurenic acid (KYNA) production
• Increased GPR35 activation (KYNA activates GPR35)
• Decreased iNOS expression

Figure 2 from ref 6 Wirthgen et al (2018).


Is this what is going on in ME macrophages???:

• Decreased IDO activity
• Decreased KYNA production
• Decreased GPR35 activation
• Increased iNOS expression

References:

1) iNOS signaling: https://www.qiagen.com/us/shop/genes-and-pathways/pathway-details/?pwid=252

2) Whole Genome Sequencing and Analysis of ME/CFS https://www.youtube.com/watch?v=nIJX-Q7w_Z4

3) Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issuehttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287

4) Sweetman et al: Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Sweetman et al: Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738418820402. doi: 10.1177/2058738418820402.
https://www.ncbi.nlm.nih.gov/pubmed/30791746

5) Kashi AA Davis RW and, Phair RD: The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS. Diagnostics (Basel). 2019 Jul 26;9(3). pii: E82. doi: 10.3390/diagnostics9030082. https://www.mdpi.com/2075-4418/9/3/82

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

6) Wirthgen E Hoeflich A, Rebl A, Günther J.: Kynurenic Acid: The Janus-Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions
Front Immunol. 2018 Jan 10;8:1957. doi: 10.3389/fimmu.2017.01957. eCollection 2017.
https://www.frontiersin.org/articles/10.3389/fimmu.2017.01957/full