onsdag den 3. oktober 2018

Is STING involved in ME?

Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling
Abstract:The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi–Goutières syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in infancy (SAVI). The involvement of STING in these diseases points to an unmet need for the development of agents that inhibit STING signaling. Here, we report that endogenously formed nitro-fatty acids can covalently modify STING by nitro-alkylation. These nitro-alkylations inhibit STING palmitoylation, STING signaling, and subsequently, the release of type I IFN in both human and murine cells. Furthermore, treatment with nitro-fatty acids was sufficient to inhibit production of type I IFN in fibroblasts derived from SAVI patients with a gain-of-function mutation in STING. In conclusion, we have identified nitro-fatty acids as endogenously formed inhibitors of STING signaling and propose for these lipids to be considered in the treatment of STING-dependent inflammatory disease (1).
The gene TMEM173 encodes STING.
TMEM173 is hypermethylated (genic location: body, p-value = 4,53E-05, FDR =  0,000816) in peripheral blood mononuclear cells (PBMC) from ME patients compared to controls (2).

TMEM173 is differentially methylated (genic location: 3'UTR, p-value = 7,25E-05, FDR = 0,000184) in PBMC from ME patient subtypes (3).

This DNA methylation pattern is related to degree of disease and quality of life in the ME patients (2, 3).

Is STING (TMEM173) involved in the pathomechanism in ME patient subtypes?

ME patents are metabolic reprogrammed (4, 5, 6, 7). Is a downregulated Nrf2 involved in a STING-pathomechanism in ME? Read about Nrf2 and STING in:

Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming

The transcription factor Nrf2 is a critical regulator of inflammatory responses. If and how Nrf2 also affects cytosolic nucleic acid sensing is currently unknown. Here we identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells. Here, Nrf2 activation decreases STING expression and responsiveness to STING agonists while increasing susceptibility to infection with DNA viruses. Mechanistically, Nrf2 regulates STING expression by decreasing STING mRNA stability. Repression of STING by Nrf2 occurs in metabolically reprogrammed cells following TLR4/7 engagement, and is inducible by a cell-permeable derivative of the TCA-cycle-derived metabolite itaconate (4-octyl-itaconate, 4-OI). Additionally, engagement of this pathway by 4-OI or the Nrf2 inducer sulforaphane is sufficient to repress STING expression and type I IFN production in cells from patients with STING-dependent interferonopathies. We propose Nrf2 inducers as a future treatment option in STING-dependent inflammatory diseases (8).

Fedtstof kan stoppe immunforsvar, der løber løbsk


1) Anne Louise Hansen et al: Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling
PNAS published ahead of print July 30, 2018 https://doi.org/10.1073/pnas.1806239115

2) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

3) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015
    4)  Naviaux et al: Metabolic features of CFS. www.pnas.org/cgi/doi/10.1073/pnas.1607571113

    5) Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371.
      6) Nagy-Szakal et al: Insights into ME/CFS phenotypes through comprehensive metabolomics. Nat Sci Rep 2018, 8.
        7) Reuter and Evans: Long-chain acylcarnitine deficiency in patients with CFS. Potential involvement of altered carnitine palmitoyltransferase-I-activity. J. Int. Med. 2011, 270.

        8)  David Olangnier et al: Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming
        Nature Communicationsvolume 9, Article number: 3506 (2018)

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