ATP and Its Metabolite Adenosine as Regulators of Dendritic Cell Activity. Extracellular ATP acts as a “danger” signal and stimulates immune responses, i.e. by inflammasome activation. Its degradation product Ado on the other hand acts rather anti-inflammatory, as it down regulates functions of dendritic cells (DCs) and dampens T cell activation and cytokine secretion.
https://www.frontiersin.org/articles/10.3389/fimmu.2018.02581/full
The IFN-induced differentiation of DCs (dendritic cells) is irreversible and, in contrast to that driven by GM-CSF and IL-4, persists upon removal of the cytokines. IFN-DCs produced lower levels of IL-12p70 and higher levels of IFN-alpha, IL-4, and IL-10 than IL-4-DCs. As a consequence of this different pattern of cytokine secretion, IFN-DCs induced T cells to produce type 1 (IFN-gamma) and type 2 (IL-4 and IL-10) cytokines, and as expected, IL-4-DCs induced only Th1 differentiation. IFN-α can bridge innate and adaptive immunity through its effects on DC differentiation/activation, skewing DC functions towards the priming and expansion of protective antitumor immune responses
https://pubmed.ncbi.nlm.nih.gov/14525963/ In addition to IFN-α, the combination of GM-CSF and IFN-β turned out to be very efficient in inducing monocyte differentiation into DCs endowed with phenotypic features very similar to those observed in the presence of IFN-α
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073125/ Side note: The irreversible differentiation is an additional potential lead to the longer term effects separate from loss of orexin neurons or lowering of orexin.
IFN-α induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p = 0.011 for IL-6 and p = 0.001 for IL-10)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350004/ It also lowers orexin, however there are other pathways that lead to orexin.
type I IFNs can exhibit beneficial effects, including antitumor and antiviral activities, but also adverse effects leading to auto-reactive CD8+ T cell responses or immune suppression by inhibiting virus-specific CD4+ T cell responses. Notably, this peculiar type of IFN-induced inhibitory effect, which may apparently be in contrast with the general role of type I IFNs as enhancers of protective immune responses, is associated with high serum levels and sustained IFN signature occurring during persistent virus infections or after prolonged IFN therapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073125/
in the fecal metabolome, the % butyrate was increased in the NoPEM group compared with both the PEM and control groups
... Importantly, histone deacetylase 2 (HDAC2) was ~four fold higher and HDAC3 was ~two-fold higher, in ME/CFS cases compared with controls
https://www.mdpi.com/2075-4418/9/3/70/htm
Perhaps try sodium butyrate, Butyrate also inhibits histone deacetylase activity (HDAC)
https://www.ncbi.nlm.nih.gov/pubmed/12840228 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333934/
Previously, a molecular switch from Th2 to Th1 cell phenotype by restoring the histone acetylation at the
Ifnγ and
Tbx21 loci was observed for human T cells treated with HDAC inhibitors
https://www.nature.com/articles/s41598-018-32860-x Low butyrate levels may even impact energy production by decreasing the conversion of pyruvate to acetyl-CoA – the main substrate for aerobic energy production in the Krebs cycle.
Elevated levels of systemic IL-10 have been associated with several chronic viral infections, including HCV, EBV, HCMV and LCMV. In the chronic LCMV infection model, both elevated IL-10 and enhanced infection of dendritic cells (DCs) are important for viral persistence. This report highlights the relationship between enhanced viral tropism for DCs and the induction of IL-10 in CD4 T cells, which we identify as the most frequent IL-10-expressing cell type in chronic LCMV infection. Here we report that infected CD8αneg DCs express elevated IL-10, induce IL-10 expression in LCMV specific CD4 T cells, and suppress LCMV-specific T cell proliferation. DCs exposed in vivo to persistent LCMV retain the capacity to stimulate CD4 T cell proliferation but induce IL-10 production by both polyclonal and LCMV-specific CD4 T cells. Our study delineates the unique effects of direct infection versus viral exposure on DCs. Collectively these data point to enhanced infection of DCs as a key trigger of the IL-10 induction cascade resulting in maintenance of elevated IL-10 expression in CD4 T cells and inhibition of LCMV-specific CD4 and CD8 T cell proliferation.
https://pubmed.ncbi.nlm.nih.gov/24613988/
@serg1942
. I like it.
